Health Benefits of Exercise

Gregory N. Ruegsegger1 and Frank W. Booth1,2,3,4

1
Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211
2
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65211
3
Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri 65211
4
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
Correspondence: boothf@missouri.edu

Overwhelming evidence exists that lifelong exercise is associated with a longer health span,
delaying the onset of 40 chronic conditions/diseases. What is beginning to be learned is the
molecular mechanisms by which exercise sustains and improves quality of life. The current
review begins with two short considerations. The first short presentation concerns the effects
of endurance exercise training on cardiovascular fitness, and how it relates to improved
health outcomes. The second short section contemplates emerging molecular connections
from endurance training to mental health. Finally, approximately half of the remaining
review concentrates on the relationships between type 2 diabetes, mitochondria, and en-
durance training. It is now clear that physical training is complex biology, invoking polygen-
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ic interactions within cells, tissues/organs, systems, with remarkable cross talk occurring
among the former list.

he aim of this introduction is briefly to cause of chronic diseases and death (Mokdad
T document facts that health benefits of phys-
ical activity predate its readers. In the 5th cen-
et al. 2004).
Published in 1953, Jeremy N. Morris and
tury BC, the ancient physician Hippocrates stat- colleagues conducted the first rigorous epide-
ed: “All parts of the body, if used in moderation miological study investigating physical activity
and exercised in labors to which each is accus- and chronic disease risk, in which coronary
tomed, become thereby healthy and well devel- heart disease (CHD) rates were increased in
oped and age slowly; but if they are unused and physically inactive bus drivers versus active con-
left idle, they become liable to disease, defective ductors (Morris et al. 1953). Since this pioneer-
in growth and age quickly.” However, by the 21st ing report, a plethora of evidence shows that
century, the belief in the value of exercise for physical inactivity is associated with the devel-
health has faded so considerably, the lack of opment of 40 chronic diseases (Table 1), includ-
exercise now presents a major public health ing major noncommunicable diseases such as
problem (Fig. 1) (Booth et al. 2012). Similarly, type 2 diabetes (T2D) and CHD, and as prema-
the lack of exercise was classified as an actual ture mortality (Booth et al. 2012).

Editors: Juleen R. Zierath, Michael J. Joyner, and John A. Hawley

Additional Perspectives on The Biology of Exercise available at www.perspectivesinmedicine.org
Copyright # 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a029694
Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694

1
 G.N. Ruegsegger and F.W. Booth

Cause of disease
Physical inactivity

Modulators
Prevention/treatment Age, diet,
Physical activity gender,
genetics, etc.

Disease risk factors

Dyslipidemia, hypertension,
hyperglycemia, visceral obesity, chronic
proinflammation, insulin resistance

Chronic disease
Type 2 diabetes, cardiovascular
disease, etc.

Reduced quality of life, premature death

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Figure 1. Simplistic overview of how physical activity can prevent the development of type 2 diabetes and one of
its complications, cardiovascular disease. Physical inactivity is an actual cause of type 2 diabetes, cardiovascular
disease, and tens of other chronic conditions (Table 1) via interaction with other factors (e.g., age, diet, gender,
and genetics) to increase disease risk factors. This leads to chronic disease, reduced quality of life, and premature
death. However, physical activity can prevent and, in some cases, treat disease progression associated with
physical inactivity and other genetic and environmental factors.

In this review, we highlight the far-reaching (commonly measured by maximal oxygen up-
health benefits of physical activity. However, take, VO2max) (Blair et al. 1989). For example,
note that the studies cited here represent only a Myers et al. (2002) showed that each 1 metabol-
fraction of the .100,000 studies showing posi- ic equivalent (1 MET) increase in exercise-test
tive associations between the terms “exercise” performance conferred a 12% improvement in
and “health.” In addition, we discuss how exercise survival, stating that “VO2max is a more power-
promotes complex integrative responses that ful predictor of mortality among men than oth-
lead to multisystem responses to exercise, an un- er established risk factors for cardiovascular dis-
derappreciated area of medical research. Finally, ease (CVD).” Low CRF is also well established as
we consider how strategies that “mimic” parts of an independent risk factor of T2D (Booth et al.
exercise training compare with physical exercise 2002) and CVD morbidity and mortality (Ko-
for their potential to combat metabolic disease. dama et al. 2009; Gupta et al. 2011). Similarly,
Kokkinos et al. (2010) reported that men who
transitioned from having low to high CRF de-
EXERCISE IMPROVES CARDIORESPIRATORY
creased their mortality risk by 50% over an 8-
FITNESS
yr period, whereas men who transitioned from
There is arguably no measure more important having high to low CRF increased their mortal-
for health than cardiorespiratory fitness (CRF) ity risk by 50%.

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 Health Benefits of Exercise

Table 1. Worsening of 40 conditions caused by the lectively bred for high or low intrinsic aerobic
lack of physical activity with growth, maturation, capacity show that rats bred for high capacity,
and aging throughout life span
which are also more physically active, have
1. Accelerated biological aging/premature death 28% – 42% increases in life span compared to
2. Aerobic (cardiorespiratory) fitness (VO2max) low-capacity rats (Koch et al. 2011). Endurance
3. Arterial dyslipidemia exercise is well recognized to improve CRF and
4. Balance
cardiometabolic risk factors. Exercise improves
5. Bone fracture/falls
6. Breast cancer
numerous factors speculated to limit VO2max
7. Cognitive dysfunction including, but not restricted to, the capacity to
8. Colon cancer transport oxygen (e.g., cardiac output), oxygen
9. Congestive heart failure diffusion to working muscles (e.g., capillary
10. Constipation density, membrane permeability, muscle myo-
11. Coronary (ischemic) heart disease globin content), and adenosine triphosphate
12. Deep vein thrombosis (ATP) generation (e.g., mitochondrial density,
13. Depression and anxiety protein concentrations).
14. Diverticulitis Data from the HERITAGE Family Study has
15. Endometrial cancer provided some of the first knowledge of genes
16. Endothelial dysfunction
associated with VO2max plasticity because of en-
17. Erectile dysfunction
18. Gallbladder diseases
durance-exercise training. Following 6 wk of cy-
19. Gestational diabetes cling training at 70% of pretraining VO2max,
20. Hemostasis Timmons et al. (2010) performed messenger
21. Hypertension RNA (mRNA) expression microarray profiling
to identify molecules potentially predicting
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22. Immunity
23. Insulin resistance VO2max training responses, and then assessed
24. Large arteries lose more compliance with aging these molecular predictors to determine wheth-
25. Metabolic syndrome er DNA variants in these genes correlated with
26. Nonalcoholic fatty liver disease VO2max training responses. This approach
27. Obesity identified 29 mRNAs in skeletal muscle and
28. Osteoarthritis
11 single-nucleotide polymorphisms (SNPs)
29. Osteoporosis
30. Ovarian cancer
that predicted 50% and 23%, respectively,
31. Pain of the variability in VO2max plasticity following
32. Peripheral artery disease aerobic training (Timmons et al. 2010). Intrigu-
33. Preeclampsia ingly, pretraining levels of these mRNAs were
34. Polycystic ovary syndrome greater in subjects that achieved greater in-
35. Prediabetes creases in VO2max following aerobic training,
36. Rheumatoid arthritis and of the 29 mRNAs, .90% were unchanged
37. Sarcopenia with aerobic training, suggesting that alternative
38. Stroke exercise intervention paradigms or pharmaco-
39. Tendons being less stiff logical strategies may be needed to improve
40. Type 2 diabetes
VO2max in individuals with a low responder pro-
The breadth of the list implies that a single molecular file for the identified predictor genes (Timmons
target will not substitute for appropriate daily physical
activity to prevent the loss of all listed items.
et al. 2010). Keller et al. (2011) found that, in
response to endurance training, improvements
in VO2max were associated with effectively up-
Importantly then, from the above para- regulating proangiogenic gene networks and
graph, physical activity and inactivity are major miRNAs influencing the transcription factor–
environmental modulators of CRF, increasing directed networks for runt-related transcription
and decreasing it, respectively, often through factor 1 (RUNX1), paired box gene 3 (PAC3),
independent pathways. Findings from rats se- and sex-determining region Y box 9 (SOX9).

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 G.N. Ruegsegger and F.W. Booth

Collectively, these results led the investigators to tions/set  2 sec/contraction  3 sets/day)

speculate that improvements in skeletal muscle  2 days/wk) ¼ 96 sec]. As of 2016, one opin-
oxygen sensing and angiogenesis are primary ion from Sarzynski et al. (2016) for the molec-
determinates in training responses in VO2max ular mechanisms by which endurance exercise
(Keller et al. 2011). drives VO2max include, but are not limited to,
Clinically important concepts have emerged calcium signaling, energy sensing and parti-
from the pioneering HERITAGE Family Study. tioning, mitochondrial biogenesis, angiogene-
One new clinical concept is that a threshold sis, immune functions, and regulation of au-
dose – response relationship influences the per- tophagy and apoptosis.
centage of subjects responding with an increase Perhaps more importantly, lifelong aerobic
in VO2max to endurance training volumes (with exercise training preserves VO2max into old age.
volume being defined here as the product of CRF generally increases until early adulthood,
intensity  duration), as previously published then declines the remainder of life in sedentary
(Slentz et al. 2005, 2007). Ross et al. (2015) later humans (Astrand 1956). The age-related de-
extended the aforementioned Slentz et al. stud- cline in VO2max is not trivial, as Schneider
ies. After a 24-wk-long endurance training study (2013) reported a 40% decline in healthy
(Ross et al. 2015), percentages of women and males and females spanning from 20 to 70 yr
men identified as nonresponders to the training of age. However, cross-sectional data show
(i.e., defined as not increasing their VO2peak) that with lifelong aerobic exercise training,
progressively fell inversely to a two stepwise pro- trained individuals often have the same VO2max
gressive increase in endurance-exercise training as a sedentary individual four decades younger
volume, as described next. Thirty-nine percent (Booth et al. 2012). Myers et al. (2002) found
(15 of 39) of training subjects did not increase that low estimated VO2max increases mortality
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their VO2peak in response to the low-amount, 4.5-fold compared to high estimated VO2max.
low-intensity training; 18% (9 of 51) had no They concluded, “Exercise capacity is a more
increase in VO2peak in the group having high- powerful predictor of mortality among men
amount, low-intensity training; and 0% (0 of than other established risk factors for cardiovas-
31) who underwent high-amount, high-inten- cular disease.” Given the strong association be-
sity training did not increase their VO2peak. A tween CRF, chronic disease, and mortality, we
biological basis for the dose – response rela- feel identifying the molecular transducers that
tionship in the previous sentence could be cause age-related reductions in CRF may have
made from an analysis of interval training (IT) profound implications for improving health
and IT/continuous-training studies published span and delaying the onset of chronic disease.
from 1965 to 2012 (Bacon et al. 2013). A second In two of our recent papers, transcriptomics was
older concept is being reinvigorated; Bacon et al. performed on the triceps muscle (Toedebusch
(2013) indicate that different endurance-exer- et al. 2016) and on the cardiac left ventricle
cise intensities and durations are needed for dif- (Ruegsegger et al. 2017). We were addressing
ferent systems in the body. They suggest that the question of what molecule initiates the be-
very short periods of high-intensity endur- ginning of the lifelong decline in aerobic capac-
ance-type exercise may be needed to reach a ity with aging. Aerobic capacity (VO2max) in-
threshold for peripheral metabolic adaptations, volves, at a minimum, the next systems/
but that longer training durations at lower in- tissues, as oxygen travels through the mouth,
tensities are required to see large changes in airways, pulmonary membrane, pulmonary cir-
maximal cardiac output and VO2max. culation, left heart, aorta/arteries/capillaries,
A comparable example exists for resistance and sarcoplasm/myoglobin to mitochondria.
training. Maximal resistance loads require a We allowed female rats access, or no access, to
minimum of 2 min/per wk for each muscle running wheels from 5 to 27 wk of age. Surpris-
group recruited by a specific maneuver to ob- ingly, voluntary running had no effect on the
tain a strength training adaptation [(8 contrac- delay in the beginning of the lifetime decrease in

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 Health Benefits of Exercise

VO2max. Our skeletal muscle transcriptomics tiation, migration, dendritic arborization, and
elicited no molecular targets, whereas gene net- synaptic plasticity (Park and Poo 2013). In rat
works suggestive of influencing maximal stroke hippocampus, regular exercise promotes a pro-
volume were identified in the left ventricle tran- gressive increase in BDNF protein for up to at
scriptomics (Ruegsegger et al. 2017). least 3 mo (Berchtold et al. 2005). In an opposite
Publications concerning the effects of exer- manner, BDNF mRNA in the hippocampus is
cise on the brain (from 54 to 216 papers listed rapidly decreased by the cessation of wheel run-
on PubMed from 2007 to 2016) have increased ning, suggesting BDNF expression is tightly re-
400%. In addition, a 2016 study (Schuch et al. lated to exercise volume (Widenfalk et al. 1999).
2016) of three previous papers reported that Findings by Wrann et al. (2013) highlight
humans with low- and moderate-CRF had one mechanism by which endurance exercise
76% and 23%, respectively, increased risk of may up-regulate BDNF expression. To summa-
developing depression compared to high CRF rize, Wrann et al. (2013) noted that exercise
in three publications. With this forming trend, increases the activity of the estrogen-related
the next section will consider exercise and brain receptor a (ERRa)/peroxisome proliferator-
health. activated receptor g coactivator 1a (PGC-1a)
complex, in turn increasing levels of the exer-
cise-secreted factor FNDC5 in skeletal muscle
EXERCISE IMPROVES MENTAL HEALTH
and the hippocampus, whose cleavage products
Many studies support physical activity as a non- provide beneficial effects in the hippocampus
invasive therapy for mental health improve- by increasing BDNF gene expression. While fu-
ments in cognition (Beier et al. 2014; Bielak et ture research should determine whether the
al. 2014; Tian et al. 2014), depression (Kratz et FNDC5 cleavage-product was produced locally
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al. 2014; McKercher et al. 2014; Mura et al. in hippocampal neurons or was secreted into
2014), anxiety (Greenwood et al. 2012; Nishi- the circulation, this finding eloquently displays
jima et al. 2013; Schoenfeld et al. 2013), neuro- one mechanism responsible for brain health
degenerative diseases (i.e., Alzheimer’s and Par- benefits following exercise. Similarly, work by
kinson’s disease) (Bjerring and Arendt-Nielsen van Praag and colleagues suggests that exercise
1990; Mattson 2014), and drug addiction (Zleb- or pharmacological activation of AMP-activat-
nik et al. 2012; Lynch et al. 2013; Peterson et al. ed protein kinase (AMPK) in skeletal muscle
2014). In 1999, van Praag et al. (1999) showed enhances indices of learning and memory, neu-
the survival of newborn cells in the adult mouse rogenesis, and gene expression related to mito-
dentate gyrus, a hippocampal region important chondrial function in the hippocampus (Kobilo
for spatial recognition, is enhanced by volun- et al. 2011, 2014; Guerrieri and van Praag 2015).
tary wheel running. Similarly, spatial pattern Insulin-like growth factor 1 (IGF-1), is cen-
separation and neurogenesis in the dentate gy- tral to many exercise-induced adaptations in the
rus are strongly correlated in 3-mo-old mice brain. Like BDNF, physical activity increases cir-
following 10 wk of voluntary wheel running culatory IGF-1 levels and both exercise and in-
(Creer et al. 2010), and the development of new fusion of IGF-1 increase BrdUþ cell number and
neurons in the dentate gyrus is coupled with the survivability in the hippocampus (Trejo et al.
formation of new blood vessels (Pereira et al. 2001). Similarly, the protective effects of exer-
2007). Many exercise-related improvements in cise on various brain lesions are nullified by
cognitive function have been associated with anti-IGF-1 antibody (Carro et al. 2001).
local and systemic expression of growth factors In 1979, Greist et al. (1979) provided evi-
in the hippocampus, notably, brain-derived dence that running reduced depression symp-
neurotrophic factor (BDNF) (Neeper et al. toms similarly to psychotherapy. However, the
1995; Cotman and Berchtold 2002). BDNF pro- precise mechanisms by which exercise prevents
motes many developmental functions in the and/or treats depression remain largely un-
brain, including neuronal cell survival, differen- known. Of the proposed mechanisms, increases

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 G.N. Ruegsegger and F.W. Booth

in the availability of brain neurotransmitters cases of T2D would be present in 2050. Unfor-
and neurotrophic factors (e.g., BDNF, dopa- tunately, the 2001 prediction of 29 million was
mine, glutamate, norepinephrine, serotonin) reached in 2012! For 2012, the American Dia-
are perhaps the best studied. For example, tyro- betes Association reported that 29 million
sine hydroxylase (TH) activity, the rate-limiting Americans had diagnosed and undiagnosed
enzyme in dopamine formation, in the stria- T2D, which was 9% of the American population
tum, an area of the brain’s reward system, is (Dwyer-Lindgren et al. 2016). More rapid in-
increased following 7 days of treadmill running creases in T2D are now predicted by the CDC
in an intensity-dependent manner (Hattori than in the previous estimate. The CDC now
et al. 1994). Voluntary wheel running is also predicts a doubling or tripling in T2D in 2050.
highly rewarding in rats, and voluntary wheel The tripling would mean that one out of three
running in rats lowers the motivation to self- U.S. adults would have T2D in their lifetime by
administer cocaine, suggesting exercise may be 2050 (Boyle et al. 2010), which would be .100
a viable strategy in the fight against drug addic- million U.S. cases. The International Diabetes
tion (Larson and Carroll 2005). Federation (IDF) reports T2D cases worldwide.
Similar to the above examples, secreted fac- In 2015, the IDF reported that 344 and 416 mil-
tors from skeletal muscle have been linked to the lion North American (including Caribbean)
regulation of depression. Agudelo et al. (2014) and worldwide adults, respectively, had T2D.
showed that exercise training in mice and hu- Furthermore, the IDF predicts for 2040 that
mans, and overexpression of skeletal muscle 413 and 642 million, respectively, will have
PGC-1a1, leads to robust increases in kynure- T2D. In sum, T2D is now pandemic, and the
nine amino transferase (KAT) expression in pandemic will increase in numbers without cur-
skeletal muscle, an enzyme whose activity pro- rent apparent action within the general public.
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tects from stress-induced increases in depres-

sion in the brain by converting kynurenine
Type 2 Diabetes Prevalence Is Based on a
into kynurenic acid. Additionally, overexpres-
Strong Genetic Predisposition
sion of PGC-1a1 in skeletal muscle left mice
resistant to stress, as evaluated by various behav- The Framingham study found that T2D risk in
ioral assays indicative of depression (Agudelo offspring was 3.5-fold and sixfold higher for a
et al. 2014). Simultaneously, they report gene single and two diabetic parent(s), respectively,
expression related to synaptic plasticity in the as compared to nondiabetic offspring (Meigs
hippocampus, such as BDNF and CamkII, were et al. 2000). Thus, T2D is gene-based.
unaffected by chronic mild stress compared to Noncoding regions of the human genome
wild-type mice. Collectively, these findings sug- contain .90% of the .100 variants associated
gest exercise-induced increases in skeletal mus- with both T2D and related traits that were ob-
cle PGC-1a1 may be an important regulator of served in genome-wide association studies
KAT expression in skeletal muscle, which, via (Scott et al. 2016). Another 2016 paper (Kwak
modulation in plasma kynurenine levels, may and Park 2016) lists at least 75 independent ge-
alleviate stress-induced depression and pro- netic loci that are associated with T2D. Taken
mote hippocampal neuronal plasticity. together, T2D is a complex genetic disease (Scott
et al. 2016).

TYPE 2 DIABETES, MITOCHONDRIA,

AND EXERCISE Type 2 Diabetes Is Modulated by Lifestyle,
with Exercise as the More Powerful Lifestyle
T2D Predictions Show a Pandemic Factor
In a 2001 Diabetes Care article (Boyle et al. Three large-scale epidemiological studies have
2001), investigators at the U.S. Centers for Dis- been performed on prediabetics, each in a dif-
ease Control (CDC) predicted 29 million U.S. ferent geographical location. The first study,

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 Health Benefits of Exercise

and only study to have separate study arms for signaling pathway at AS160 and TBC1 domain
diet and exercise, was in China. The pure exer- family member 1 (TBC1D1) (Deshmukh et al.
cise intervention group had a 46% reduction in 2006; Maarbjerg et al. 2011), facilitating GLUT4
the onset of T2D, relative to the nontreated expression translocation to the plasma mem-
group, after 6 yr of the study (Pan et al. 1997). brane independent of the insulin receptor. We
Diet alone reduced T2D by 31% in the Chinese contend that exercise could be considered as a
study. The second study on T2D was the Finnish very powerful tool to primarily attenuate the
Diabetes Prevention Study. It found a 58% re- T2D pandemic.
duction in T2D in the lifestyle intervention
(combined diet and exercise) in its 522 predia-
Complex Biology of T2D Interactions with the
betic subjects after a mean study duration of
Complex Biology of Exercise
3.2 yr (Tuomilehto et al. 2001). The latest of
the three studies was in the U.S. Diabetes Pre- An important consideration from the above is
vention Program. The large randomized trial (n that T2D is such a genetically complex disease
¼ 3150 prediabetics) was stopped after 2.8 yr, that a single gene has not been proven to be
because of harm to the control group. T2D sufficiently causal to be effective, at this stage
prevalence in the high-risk adults was reduced in time, to be a successful target for pharmaco-
by 58% with intensive lifestyle (diet and exer- logical treatment. The expectation for a single
cise) intervention, whereas the drug arm (met- molecule target has been met for infectious dis-
formin) of the study only reduced T2D by 31%, eases, which are often monogenic diseases. For
both compared to the noninnervation group example, a vaccine against smallpox was highly
(Knowler et al. 2002). Thus, if differences in successful. Edward Jenner in 1796 produced
genetics in the above three differing ethnicities the first successful vaccine. An important fact
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are not a factor, combined exercise and diet re- is that exercise is genetically complex. The
main more effective in T2D prevention than the literature allows us to speculate that exercise is
drug metformin two decades ago. at least as genetically complex as the approxi-
mately 75 genes associated with T2D (Kwak
and Park 2016). An example indicating that ex-
Exercise Increases Glucose by Signaling
ercise is complex biology follows. RNA sequenc-
Independent of the Insulin Receptor
ing analysis of all 119 vastus lateralis muscle
A single exercise bout increases glucose uptake biopsies found that endurance training for 4
by skeletal muscle, sidestepping the insulin re- days/wk for 12 wk produced the differential ex-
ceptor and thus insulin resistance in T2D pa- pression of 3404 putative isoforms, belonging to
tients (Holloszy and Narahara 1965; Goodyear 2624 different genes, many associated with oxi-
and Kahn 1998; Holloszy 2005). After insulin dative ATP production in 23 women and men
binding to its receptor, insulin initiates a down- aged 29 yr old (Lindholm et al. 2016). Our no-
stream signaling cascade of tyrosine autophos- tion is that over 2600 genes suggests complex
phorylation of insulin receptor, insulin receptor biology.
substrate 1 (IRS-1) binding and phosphoryla-
tion, activation of a PI3K-dependent pathway,
A “Case-Type” Study of the Molecular
including key downstream regulators protein
Underpinnings of Exercise, Mitochondria,
kinase B (Akt) and the Akt substrate of
and T2D Interactions
160 kDa (AS160), ultimately promoting glu-
cose transporter 4 (GLUT4) translocation to A PubMed search for the terms “diabetes mito-
the plasma membrane (Rockl et al. 2008; Stan- chondria exercise molecular” elicited 74 papers.
ford and Goodyear 2014). Despite normal We arbitrarily selected some of the most recent
GLUT4 levels, insulin fails to induce GLUT4 50 (spanning from mid-2014 into January
translocation in T2D (Zierath et al. 2000). How- 2017), with the assumption they would be rep-
ever, exercise activates a downstream insulin- resentative of any other papers that we did not

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 G.N. Ruegsegger and F.W. Booth

find in our search. Papers fell into our two ar- for other changes that have previously been
bitrary categories of single gene studies versus recorded before the increase in total PGC-1a
“omic”-type studies. First, subcategories of postexercise.
studies that develop themes will be arbitrarily
presented. 4. Mice with knockout of the kinin B1 receptor
gene had higher mitochondrial DNA quan-
tification and of mRNA levels of genes relat-
Recent Studies Show Single Gene
Manipulation Alters Mitochondrial Level ed to mitochondrial biogenesis in soleus and
and Running Performance gastrocnemius muscles and had higher exer-
cise times to exhaustion, but did not have
Numerous reports in the past couple of years higher VO2max (Reis et al. 2015).
observed that single gene manipulations in-
crease mitochondrial gene expression and activ- 5. Mice do not normally express cholesteryl es-
ity, which was also associated with increased ter transfer protein (CETP), which is a lipid
exercise performance/capacity. A few of these transfer protein that shuttles lipids between
are presented below: serum lipoproteins and tissues. Overex-
pression of CETP in mice after 6 wk on a
1. Irisin was shown to increase oxidative me- high-fat diet increased treadmill running du-
tabolism in myocytes and increase PGC-1a ration and distance, mitochondrial oxidation
mRNA and protein (Vaughan et al. 2014), of glutamate/malate, but not palmitoyl-
which extends the first observation made carnitine oxidation, and doubled PGC-1a
earlier in adipose tissue by Spiegelman (Bos- mRNA concentration (Cappel et al. 2015).
trom et al. 2012).
6. The myokine musclin is a peptide secreted
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2. Patients with impaired glucose tolerance from exercising muscle during treadmill
underwent low-intensity exercise training. running. Removal of musclin release during
Patients whose mitochondrial markers in- running results in lowered VO2max, lower
creased to levels that were measured in a sep- skeletal muscle mitochondrial content and
arate cohort of nonexercised healthy individ- respiratory complex protein expression,
uals recovered normal glucose tolerance and reduced exercise tolerance (Subbotina
(Osler et al. 2015). In opposition, those pa- et al. 2015).
tients whose mitochondria markers did not
improve, remained with impaired glucose 7. Lactate dehydrogenase B (LDHB), which
tolerance. produces pyruvate from lactate, was overex-
pressed in mouse skeletal muscle. Increases
3. In 2003, muscle PGC-1a mRNA was shown in markers of skeletal muscle mitochondria
to be induced by endurance-exercise training were associated with increased running dis-
in human skeletal muscle (Short et al. 2003). tance in a progressive speed test, and in-
PGC-1a was shown to have multiple iso- creased peak VO2 (Liang et al. 2016).
forms (Lin et al. 2002). After a 60-min cy-
cling bout, human vastus lateralis biopsies 8. Another example of endurance-type exercise
were taken from both sexes in their mid- adaptations is the 2016 paper that transcrip-
20s. Additional biopsies were taken 30 min, tion factor EB (TFEB) regulates metabolic
and at 2, 6, and 24 hr postexercise. At 30 min flexibility in skeletal muscle independent of
postexercise, PGC-1a-ex1b mRNA and PGC-1a during endurance-type exercise
PGC-1a mRNA increased 468- and 2.4- (Mansueto et al. 2017). Lack of metabolic
fold, respectively, whereas PGC-1a-ex1b flexibility, termed “metabolic inflexibility,”
protein and PGC-1a protein increased 3.1- is important because it is common in T2D.
fold and no change, respectively. Gidlund One definition of metabolic inflexibility is its
et al. (2015) interprets the above data as im- inability to rapidly switch between glucose
plying PGC-1a-ex1b could be responsible and fatty acid substrates for ATP production

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 Health Benefits of Exercise

when nutrient availability changes from high to endurance exercise. In 2002, two groups iden-
blood glucose levels immediately after a meal tified PGC-1b, a transcriptional coactivator
to decreasing below 100 mg/dl when not closely related to PGC-1a (Kressler et al. 2002;
eating for hours after a meal. A clinical Lin et al. 2002). Later in 2012, the PGC-1a4
consequence of T2D-induced metabolic in- variant of PGC-1a was found to induce skeletal
flexibility is prolonged periods of hypergly- muscle hypertrophy and strength (Ruas et al.
cemia, because skeletal muscle is more insu- 2012). The importance of the finding of a
lin insensitive in T2D. In contrast, after PGC-1a variant is that it partially explains the
sufficient endurance exercise, skeletal muscle phenotypic variation for differing types of exer-
increases its insulin sensitivity by a second cise. Since the 1970s (Holloszy and Booth 1976),
pathway that is independent of proximal it has been appreciated that the biochemical and
postreceptor insulin signaling (see Stephen- anatomical observations between endurance
son et al. 2014 for further discussion). and resistance differed. For example, Holloszy
and Booth (1976) noted in 1976 that, whereas
endurance-type exercise markedly increased
Studies Showing that Manipulation of One skeletal muscle mitochondrial density with
Signaling Molecule Does Not Alter Expression very minor increases in muscle fiber diameter,
of All Genes with Mitochondrial Functions
strength-type exercise, in contrast, increased
Found in Skeletal Muscles of Wild-Type
muscle fiber diameter without increases in skel-
Animals to Exercise Training
etal muscle mitochondrial density. Taken to-
A 2010 review article (Lira et al. 2010) concludes gether, a drug specific for PGC-1a will not likely
from gene-deletion studies that p38g MAPK/ mimic separate physical training for endurance,
PGC-1a signaling controls mitochondrial bio- strength/resistance, and coordination types of
www.perspectivesinmedicine.org

genesis’ adaptation to endurance exercise in exercise in the same subject. Thus, the common
skeletal muscle. Two studies do not completely usage of the term exercise capacity is a misnomer
agree with the conclusion in the review article. because endurance training and resistance train-
The Pilegaard laboratory published a 2008 ing were shown to have different exercise capac-
study (Leick et al. 2008) that did not confirm ity phenotypes very long ago.
their hypothesis that PGC-1a was required for In a 2015 Diabetes paper (Wong et al. 2015),
every metabolic protein adaptive increase after Muoio’s laboratory concluded that changes in
endurance-exercise training by skeletal muscle. glucose tolerance and total body fat depended
They reported that PGC-1a was not required upon how much energy is expended in con-
for endurance-training-induced increases in tracting muscle rather than muscle mitochon-
ALAS1, COXI, and cytochrome c expression drial content or substrate selection. A finding to
(Leick et al. 2008). Their interpretation, at that support the previous sentence was the glucose
time, was that molecules other than PGC-1a tolerance tests (GTTs). MCK-PGC-1a mice and
can exert exercise-induced mitochondrial adap- their nontransgenic (NT) littermates were not
tations. A second study published in 2012 ren- different in GTT, with both being the most glu-
dered a similar verdict. A 12-day program of cose intolerant after 10 wk of high-fat feeding.
endurance training led to the middle portion Adding 10 wk of voluntary wheel running to
of the gastrocnemius muscle demonstrating a the two high-fat-feed groups during the next
similar 60% increase in mitochondrial density 10-wk period (weeks 11 – 20 of the experiment)
in both wild-type and PGC-1a muscle-specific lowered the glucose intolerance, and then dur-
knockout mice (Myo-PGC-1aKO) (Rowe et al. ing weeks 21 – 30 of the experiment, glucose in-
2012). The paper concludes that PGC-1a is dis- tolerance was further lowered by adding 25%
pensable for endurance-exercise’s induction of caloric restriction with the high-fat food and
skeletal muscle mitochondrial adaptations. running during the final 10 wk. The percentage
Exercise signaling targets have actions that weight lost after 30 wk of high-fat feeding was
are independent of PGC-1a, which is specific positively related to greater running distances.

Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694 9

 G.N. Ruegsegger and F.W. Booth

No single front-runner gene candidate could To present one extreme, that most will
be identified by principle component analysis. agree, one molecule will not describe the
Taken together, the paper suggests “doubts” that 1000s of molecules adapting to aerobic, resis-
pharmacological exercise mimetics that increase tance, and coordination exercise training. On
muscle oxidative capacity will be effective the opposite extreme, many could likely agree
antiobesity and/or antidiabetic agents. Rather, that usage of the various “omics” underlying all
Muoio and investigators suggest energy expen- adaptations to physical activity will differ (i.e.,
diture by muscle contraction induces localized not be identical in most aspects) among the
shifts in energy balance inside the muscle fiber, next list: various cell types within a tissue/or-
which then initiates a broad network of meta- gan, tissues/organs, and various intensities of
bolic intermediates regulating nutrient sensing physical activity (i.e., the thresholds among
and insulin action. A further discussion of gene responses for health benefits will differ
complex biology produced by polygenicity con- because of the presence of responders and non-
tinues next. responders, or protein isoform type); during
various types cycling (circadian or menstrual);
postprandial versus fasting between meals; male
POLYGENICITY OF EXERCISE LEADS and female; child, adult, and the elderly; trained
TO COMPLEX MULTISYSTEM RESPONSES and untrained; aerobic- and resistance-exercise
TO IMPROVE HEALTH OUTCOMES types; and so forth. Others have repetitively
Multiples tissues, organs, and systems are influ- written that only 59% of the risk reduction
enced by physical activity, or the lack thereof for all forms of CVD have been shown to be
(Table 2). caused by effects through traditional factors
(Mora et al. 2007; Joyner and Green 2009).
www.perspectivesinmedicine.org

Thus, we pose the next question: what is the

Table 2. Worsening of maximal functioning in select- identity of all molecules in the yet-to-be-discov-
ed major organ/tissue/systems that are caused by the ered gap between our knowledge of single gene
lack of physical activity with growth, maturation, and
aging
functions and the totality of personalized pre-
scription of physical activity to maximize the
Organ/tissue/system loses period of life free of any chronic disease, termed
designated function, most with
health span?
Site aging after maturation
While approaches using single-gene manip-
Brain Specific types of cognition ulations are valuable tools, research must also
Brain Motor coordination and balance focus on integrating exercise-responsive mole-
Heart Maximal pumping volume/
cules into networks that maintain or improve
minute
Peripheral Maximal capacity to supply blood
health. This process will reveal complex, multi-
circulation to working muscles system, polygenic networking essential for the
Peripheral Prevention of capillary rarefaction advancement of many goals pertaining to exer-
circulation in feet cise physiology, such as tailoring exercise pre-
Skeletal muscle Less mass and strength scriptions and implementing personalized
Skeletal muscle Lower insulin sensitivity medicine. One example is the developing myo-
Pancreas Loss of b cells kine network with auto-, para-, and endocrine
Aerobic capacity Lower molecules. The first myokine interleukin (IL)-6
Bone Less mass and strength began to be described as early as 1994 by the
Liver Excessive fat storage Pedersen laboratory (Ullum et al. 1994), with a
The higher their maximal function is before the end of history of its development as the first exercise
each item’s maturation, the longer chances are that the
myokine recounted in 2007 (Pedersen et al.
quality of life will remain optimal. The breadth of the list
implies that a single molecular target will not substitute for 2007). Since their discovery, myokine action
appropriate daily physical activity to prevent the loss of all within and at a distance from their origins in
listed items. skeletal muscle have been increasingly studied,

10 Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694

 Health Benefits of Exercise

Bloodstream Bone
CNTF: inhibits osteoblasts

Breast

OSM: inhibits mammary cancer cell growth

Pancreas
IL-6: increased GLP1 secretion

Gut
IL-6: increased GLP1 secretion
Skeletal muscle
SPARC: suppressed colon tumorigenesis

Liver
Myokines

WAT
IL-6: increased lipolysis
FGF21: increased glucose uptake
Irisin: increased thermogenic program, browning
BAIBA: increased thermogenic program, browning
Metrnl: increased thermogenic program, browning

MSTN: negative regulator of muscle mass BAT

increased glucose uptake and β-oxidation
www.perspectivesinmedicine.org

IL-6:
IL-15: hypertrophy
BDNF: increased β-oxidation
Irisin: increased energy expenditure and IL-15: increased thermogenesis and β-oxidation
oxidative metabolism

Brain
IL-8: angiogenesis BDNF: learning and memory
VEGF: angiogenesis Irisin: increased hippocampal BDNF expression

Figure 2. Figure provides an illustration of myokine production by skeletal muscle for actions within or at a
distance. Myokine release promotes a high degree of intertissue cross talk. CNTF, Ciliary neurotrophic factor;
OSM, oncostatin M; IL, interleukin; BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial
growth factor. (From Schnyder and Handschin 2015; reprinted, with permission, courtesy of PMC Open
Access.)

as schematically illustrated by Schnyder and Exercise Provides Too Many Benefits to “Fit
Handschin (2015) (Fig. 2). into a Single Pill”
Similarly, maximal aerobic exercise is ac-
companied by tremendous stress on many Despite the well-known benefits of exercise,
systems, yet whole-body homeostasis is remark- most adults and many children lead relatively
ably maintained. For example, world-class en- sedentary lifestyles and are not active enough
durance athletes can increase whole-body ener- to achieve the health benefits of exercise (War-
gy production well over 20-fold (Joyner and burton et al. 2006; Fried 2016). Accelerometry
Coyle 2008), whereas maintaining blood glu- measurements suggest that .90% of U.S. indi-
cose concentrations at resting levels (Wasser- viduals .12 yr of age and 50% of children
man 2009). Intuitively, such effort would re- aged 6 – 11 yr old fail to meet U.S. Federal phys-
quire sophisticated interorgan cross talk and ical activity guidelines (Troiano et al. 2008).
polygenic integration of numerous functions. Given this incredibly low compliance, the iden-

Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694 11

 G.N. Ruegsegger and F.W. Booth

tification of genetic and/or orally active agents REFERENCES

that mimic the effects of endurance exercise
Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M,
might have high appeal for a majority of seden- Goiny M, Martinez-Redondo V, Correia JC, Izadi
tary individuals. This high appeal has led to M, Bhat M, Schuppe-Koistinen I, et al. 2014. Skeletal
recent identification/development of exercise muscle PGC-1a1 modulates kynurenine metabolism
and mediates resilience to stress-induced depression.
“mimetics.” In 2009, we set criteria for proper Cell 159: 33– 45.
usage of the term “exercise mimetic,” based Astrand PO. 1956. Human physical fitness with special ref-
upon its common usage (Booth and Laye erence to sex and age. Physiol Rev 36: 307– 335.
2009). We gave the Oxford English Dictionary’s Bacon AP, Carter RE, Ogle EA, Joyner MJ. 2013. VO2max
definition of mimetic, “A synthetic compound trainability and high intensity interval training in hu-
mans: A meta-analysis. PLoS ONE 8: e73182.
that produces the same (or a very similar) effect Beier M, Bombardier CH, Hartoonian N, Motl RW, Kraft
as another (especially a naturally occurring) GH. 2014. Improved physical fitness correlates with im-
compound.” While many exercise “mimetics” proved cognition in multiple sclerosis. Arch Phys Med
Rehabil 95: 1328–1334.
activate signaling pathways commonly associat-
Berchtold NC, Chinn G, Chou M, Kesslak JP, Cotman CW.
ed with muscle endurance, these agents have not 2005. Exercise primes a molecular memory for brain-
completely mimicked all effects for all types derived neurotrophic factor protein induction in the rat
of exercise. For example, the AMPK activator hippocampus. Neuroscience 133: 853– 861.
5-aminoimidazole-4-carboxamide ribonucleo- Bielak AA, Cherbuin N, Bunce D, Anstey KJ. 2014. Preserved
differentiation between physical activity and cogni-
tide (AICAR), when given daily to rats over a tive performance across young, middle, and older adult-
5-wk-period, did not increase maximal oxygen hood over 8 years. J Gerontol B Psychol Sci Soc Sci 69: 523–
consumption (VO2peak) in the sedentary group 532.
of rats that were forced to run to VO2peak on Bjerring P, Arendt-Nielsen L. 1990. Inhibition of histamine
skin flare reaction following repeated topical applications
treadmills, as compared to sedentary rats receiv-
www.perspectivesinmedicine.org

of capsaicin. Allergy 45: 121–125.

ing the vehicle (Toedebusch et al. 2016). Thus, in Blair SN, Kohl HWIII, Paffenbarger RSJr, Clark DG, Cooper
our opinion, the published claim (Narkar et al. KH, Gibbons LW. 1989. Physical fitness and all-cause
2008) that AICAR is an exercise mimetic is in- mortality. A prospective study of healthy men and wom-
en. JAMA 262: 2395–2401.
validated because it did not increase VO2peak.
Booth FW, Laye MJ. 2009. Lack of adequate appreciation of
While these agents may undoubtedly have physical exercise’s complexities can preempt appropriate
specific health benefits, it is currently impracti- design and interpretation in scientific discovery. J Physiol
cal to assume that all of the benefits of exercise 587: 5527– 5539.
Booth FW, Chakravarthy MV, Gordon SE, Spangenburg EE.
can be replaced by “exercise mimetics.” 2002. Waging war on physical inactivity: Using modern
molecular ammunition against an ancient enemy. J Appl
Physiol (1985) 93: 3– 30.
CONCLUDING REMARKS Booth FW, Roberts CK, Laye MJ. 2012. Lack of exercise is a
major cause of chronic diseases. Compr Physiol 2: 1143–
Exercise is a powerful tool in the fight to prevent 1211.
and treat numerous chronic diseases (Table 1). Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC,
Rasbach KA, Bostrom EA, Choi JH, Long JZ, et al. 2012.
Given its whole-body, health-promoting na- A PGC1-a-dependent myokine that drives brown-fat-
ture, the integrative responses to exercise should like development of white fat and thermogenesis. Nature
surely attract a great detail of interest as the no- 481: 463–468.
tion of “exercise is medicine” continues to its Boyle JP, Honeycutt AA, Narayan KM, Hoerger TJ, Geiss LS,
Chen H, Thompson TJ. 2001. Projection of diabetes bur-
integration into clinical settings. den through 2050: Impact of changing demography and
disease prevalence in the U.S. Diabetes Care 24: 1936–
1940.
ACKNOWLEDGMENTS Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson
DF. 2010. Projection of the year 2050 burden of diabetes
The authors disclose no conflicts of inter- in the US adult population: Dynamic modeling of inci-
dence, mortality, and prediabetes prevalence. Popul
est. Partial funding for this project was ob- Health Metr 8: 29.
tained from grants awarded to G.N.R. (AHA Cappel DA, Lantier L, Palmisano BT, Wasserman DH, Staf-
16PRE2715005). ford JM. 2015. CETP expression protects female mice

12 Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694

 Health Benefits of Exercise

from obesity-induced decline in exercise capacity. PLoS Joyner MJ, Coyle EF. 2008. Endurance exercise performance:
ONE 10: e0136915. The physiology of champions. J Physiol 586: 35– 44.
Carro E, Trejo JL, Busiguina S, Torres-Aleman I. 2001. Cir- Joyner MJ, Green DJ. 2009. Exercise protects the cardiovas-
culating insulin-like growth factor I mediates the protec- cular system: Effects beyond traditional risk factors. J
tive effects of physical exercise against brain insults of Physiol 587: 5551– 5558.
different etiology and anatomy. J Neurosci 21: 5678– Keller P, Vollaard NB, Gustafsson T, Gallagher IJ, Sundberg
5684. CJ, Rankinen T, Britton SL, Bouchard C, Koch LG, Tim-
Cotman CW, Berchtold NC. 2002. Exercise: A behavioral mons JA. 2011. A transcriptional map of the impact of
intervention to enhance brain health and plasticity. endurance exercise training on skeletal muscle pheno-
Trends Neurosci 25: 295– 301. type. J Appl Physiol (1985) 110: 46–59.
Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF,
2010. Running enhances spatial pattern separation in Lachin JM, Walker EA, Nathan DM. 2002. Reduction in
mice. Proc Natl Acad Sci 107: 2367–2372. the incidence of type 2 diabetes with lifestyle intervention
Deshmukh A, Coffey VG, Zhong Z, Chibalin AV, Hawley JA, or metformin. N Engl J Med 346: 393 –403.
Zierath JR. 2006. Exercise-induced phosphorylation of Kobilo T, Yuan C, van Praag H. 2011. Endurance factors
the novel Akt substrates AS160 and filamin A in human improve hippocampal neurogenesis and spatial memory
skeletal muscle. Diabetes 55: 1776–1782. in mice. Learn Mem 18: 103 –107.
Dwyer-Lindgren L, Mackenbach JP, van Lenthe FJ, Flaxman Kobilo T, Guerrieri D, Zhang Y, Collica SC, Becker KG, van
AD, Mokdad AH. 2016. Diagnosed and undiagnosed di- Praag H. 2014. AMPK agonist AICAR improves cogni-
abetes prevalence by county in the U.S., 1999– 2012. Di- tion and motor coordination in young and aged mice.
abetes Care 39: 1556– 1562. Learn Mem 21: 119 –126.
Fried LP. 2016. Interventions for human frailty: Physical Koch LG, Kemi OJ, Qi N, Leng SX, Bijma P, Gilligan LJ,
activity as a model. Cold Spring Harb Perspect Med doi: Wilkinson JE, Wisloff H, Hoydal MA, Rolim N, et al.
10.1101/cshperspect.a025916. 2011. Intrinsic aerobic capacity sets a divide for aging
Gidlund EK, Ydfors M, Appel S, Rundqvist H, Sundberg CJ, and longevity. Circ Res 109: 1162–1172.
Norrbom J. 2015. Rapidly elevated levels of PGC-1a-b Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M,
protein in human skeletal muscle after exercise: Explor- Sugawara A, Totsuka K, Shimano H, Ohashi Y, et al. 2009.
ing regulatory factors in a randomized controlled trial. J Cardiorespiratory fitness as a quantitative predictor of
www.perspectivesinmedicine.org

Appl Physiol (1985) 119: 374–384. all-cause mortality and cardiovascular events in healthy
Goodyear LJ, Kahn BB. 1998. Exercise, glucose trans- men and women: A meta-analysis. JAMA 301: 2024–
port, and insulin sensitivity. Annu Rev Med 49: 235– 2035.
261. Kokkinos P, Myers J, Faselis C, Panagiotakos DB, Doumas
Greenwood BN, Loughridge AB, Sadaoui N, Christianson M, Pittaras A, Manolis A, Kokkinos JP, Karasik P, Green-
JP, Fleshner M. 2012. The protective effects of voluntary berg M, et al. 2010. Exercise capacity and mortality in
exercise against the behavioral consequences of uncon- older men: A 20-year follow-up study. Circulation 122:
trollable stress persist despite an increase in anxiety fol- 790 –797.
lowing forced cessation of exercise. Behav Brain Res 233: Kratz AL, Ehde DM, Bombardier CH. 2014. Affective me-
314–321. diators of a physical activity intervention for depression
Greist JH, Klein MH, Eischens RR, Faris J, Gurman AS, in multiple sclerosis. Rehabil Psychol 59: 57– 67.
Morgan WP. 1979. Running as treatment for depression. Kressler D, Schreiber SN, Knutti D, Kralli A. 2002. The PGC-
Compr Psychiatry 20: 41–54. 1-related protein PERC is a selective coactivator of estro-
Guerrieri D, van Praag H. 2015. Exercise-mimetic AICAR gen receptor a. J Biol Chem 277: 13918– 13925.
transiently benefits brain function. Oncotarget 6: 18293– Kwak SH, Park KS. 2016. Recent progress in genetic and
18313. epigenetic research on type 2 diabetes. Exp Mol Med 48:
Gupta S, Rohatgi A, Ayers CR, Willis BL, Haskell WL, Khera e220.
A, Drazner MH, de Lemos JA, Berry JD. 2011. Cardio- Larson EB, Carroll ME. 2005. Wheel running as a predictor
respiratory fitness and classification of risk of cardiovas- of cocaine self-administration and reinstatement in fe-
cular disease mortality. Circulation 123: 1377– 1383. male rats. Pharmacol Biochem Behav 82: 590– 600.
Hattori S, Naoi M, Nishino H. 1994. Striatal dopamine Leick L, Wojtaszewski JF, Johansen ST, Kiilerich K, Comes G,
turnover during treadmill running in the rat: Relation Hellsten Y, Hidalgo J, Pilegaard H. 2008. PGC-1a is not
to the speed of running. Brain Res Bull 35: 41–49. mandatory for exercise- and training-induced adaptive
Holloszy JO. 2005. Exercise-induced increase in muscle in- gene responses in mouse skeletal muscle. Am J Physiol
sulin sensitivity. J Appl Physiol (1985) 99: 338 –343. Endocrinol Metab 294: E463– E474.
Holloszy JO, Booth FW. 1976. Biochemical adaptations to Liang X, Liu L, Fu T, Zhou Q, Zhou D, Xiao L, Liu J, Kong Y,
endurance exercise in muscle. Annu Rev Physiol 38: 273 – Xie H, Yi F, et al. 2016. Exercise inducible lactate dehy-
291. drogenase B regulates mitochondrial function in skeletal
Holloszy JO, Narahara HT. 1965. Studies of tissue perme- muscle. J Biol Chem 291: 25306–25318.
ability. X: Changes in permeability to 3-methylglucose Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM. 2002.
associated with contraction of isolated frog muscle. J Peroxisome proliferator-activated receptor g coactivator
Biol Chem 240: 3493– 3500. 1 b (PGC-1b ), a novel PGC-1-related transcription co-

Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694 13

 G.N. Ruegsegger and F.W. Booth

activator associated with host cell factor. J Biol Chem 277: behavior and impairs adult hippocampal neurogenesis
1645– 1648. in mice. Behav Brain Res 245: 34–41.
Lindholm ME, Giacomello S, Werne Solnestam B, Fischer Osler ME, Fritz T, Caidahl K, Krook A, Zierath JR,
H, Huss M, Kjellqvist S, Sundberg CJ. 2016. The impact Wallberg-Henriksson H. 2015. Changes in gene ex-
of endurance training on human skeletal muscle memo- pression in responders and nonresponders to a low-
ry, global isoform expression and novel transcripts. PLoS intensity walking intervention. Diabetes Care 38:
Genet 12: e1006294. 1154–1160.
Lira VA, Benton CR, Yan Z, Bonen A. 2010. PGC-1a regu- Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX,
lation by exercise training and its influences on muscle Lin J, Xiao JZ, Cao HB, et al. 1997. Effects of diet and
function and insulin sensitivity. Am J Physiol Endocrinol exercise in preventing NIDDM in people with impaired
Metab 299: E145– E161. glucose tolerance. The Da Qing IGT and Diabetes Study.
Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA. 2013. Diabetes Care 20: 537– 544.
Exercise as a novel treatment for drug addiction: A neu- Park H, Poo MM. 2013. Neurotrophin regulation of neural
robiological and stage-dependent hypothesis. Neurosci circuit development and function. Nat Rev Neurosci 14:
Biobehav Rev 37: 1622– 1644. 7 –23.
Maarbjerg SJ, Sylow L, Richter EA. 2011. Current under- Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. 2007.
standing of increased insulin sensitivity after exercise— Role of myokines in exercise and metabolism. J Appl
Emerging candidates. Acta Physiol (Oxf ) 202: 323– 335. Physiol (1985) 103: 1093– 1098.
Mansueto G, Armani A, Viscomi C, D’Orsi L, De Cegli R, Pereira AC, Huddleston DE, Brickman AM, Sosunov AA,
Polishchuk EV, Lamperti C, Di Meo I, Romanello V, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR,
Marchet S, et al. 2017. Transcription factor EB controls Small SA. 2007. An in vivo correlate of exercise-induced
metabolic flexibility during exercise. Cell Metab 25: 182 – neurogenesis in the adult dentate gyrus. Proc Natl Acad
196. Sci 104: 5638– 5643.
Mattson MP. 2014. Interventions that improve body and Peterson AB, Hivick DP, Lynch WJ. 2014. Dose-dependent
brain bioenergetics for Parkinson’s disease risk reduction effectiveness of wheel running to attenuate cocaine-seek-
and therapy. J Parkinsons Dis 4: 1– 13. ing: Impact of sex and estrous cycle in rats. Psychophar-
McKercher C, Sanderson K, Schmidt MD, Otahal P, Patton macology (Berl) 231: 2661– 2670.
GC, Dwyer T, Venn AJ. 2014. Physical activity patterns Reis FC, Haro AS, Bacurau AV, Hirabara SM, Wasinski F,
www.perspectivesinmedicine.org

and risk of depression in young adulthood: A 20-year Ormanji MS, Moreira JB, Kiyomoto BH, Bertoncini
cohort study since childhood. Soc Psychiatry Psychiatr CR, Brum PC, et al. 2015. Deletion of kinin B2 receptor
Epidemiol 49: 1823–1834. alters muscle metabolism and exercise performance.
Meigs JB, Cupples LA, Wilson PW. 2000. Parental transmis- PLoS ONE 10: e0134844.
sion of type 2 diabetes: The Framingham Offspring Rockl KS, Witczak CA, Goodyear LJ. 2008. Signaling
Study. Diabetes 49: 2201– 2207. mechanisms in skeletal muscle: Acute responses and
Mokdad AH, Marks JS, Stroup DF, Gerberding JL. 2004. chronic adaptations to exercise. IUBMB Life 60: 145–
Actual causes of death in the United States, 2000. 153.
JAMA 291: 1238–1245. Ross R, de Lannoy L, Stotz PJ. 2015. Separate effects of
Mora S, Cook N, Buring JE, Ridker PM, Lee IM. 2007. intensity and amount of exercise on interindividual car-
Physical activity and reduced risk of cardiovascular diorespiratory fitness response. Mayo Clin Proc 90: 1506–
events: Potential mediating mechanisms. Circulation 1514.
116: 2110–2118. Rowe GC, El-Khoury R, Patten IS, Rustin P, Arany Z. 2012.
Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. 1953. PGC-1a is dispensable for exercise-induced mitochon-
Coronary heart-disease and physical activity of work. drial biogenesis in skeletal muscle. PLoS ONE 7:
Lancet 265: 1053– 1057. e41817.
Mura G, Moro MF, Patten SB, Carta MG. 2014. Exercise Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Har-
as an add-on strategy for the treatment of major depres- rison BC, Greene NP, Wu J, Estall JL, Irving BA, et al.
sive disorder: A systematic review. CNS Spectr 19: 496 – 2012. A PGC-1a isoform induced by resistance training
508. regulates skeletal muscle hypertrophy. Cell 151: 1319–
Myers J, Prakash M, Froelicher V, Do D, Partington S, At- 1331.
wood JE. 2002. Exercise capacity and mortality among Ruegsegger GN, Toedebusch RG, Braselton JF, Childs TE,
men referred for exercise testing. N Engl J Med 346: 793 – Booth FW. 2017. Left ventricle transcriptomic analysis
801. reveals connective tissue accumulation associates with
Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo initial age-dependent decline in VO2peak from its lifetime
E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, et al. apex. Physiol Genomics 49: 53– 66.
2008. AMPK and PPARd agonists are exercise mimetics. Sarzynski MA, Ghosh S, Bouchard C. 2016. Genomic and
Cell 134: 405– 415. transcriptomic predictors of response levels to endurance
Neeper SA, Gomez-Pinilla F, Choi J, Cotman C. 1995. Ex- exercise training. J Physiol doi: 10.1113/JP272559.
ercise and brain neurotrophins. Nature 373: 109. Schneider J. 2013. Age dependency of oxygen uptake and
Nishijima T, Llorens-Martin M, Tejeda GS, Inoue K, Yama- related parameters in exercise testing: An expert opinion
mura Y, Soya H, Trejo JL, Torres-Aleman I. 2013. Cessa- on reference values suitable for adults. Lung 191: 449–
tion of voluntary wheel running increases anxiety-like 458.

14 Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694

 Health Benefits of Exercise

Schnyder S, Handschin C. 2015. Skeletal muscle as an en- time-apex VO2peak, while voluntary wheel running fails
docrine organ: PGC-1a, myokines and exercise. Bone 80: to delay its initial decline in female rats. Physiol Genomics
115–125. 48: 101– 115.
Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E. Trejo JL, Carro E, Torres-Aleman I. 2001. Circulating in-
2013. Physical exercise prevents stress-induced activa- sulin-like growth factor I mediates exercise-induced
tion of granule neurons and enhances local inhibitory increases in the number of new neurons in the adult
mechanisms in the dentate gyrus. J Neurosci 33: 7770– hippocampus. J Neurosci 21: 1628–1634.
7777.
Troiano RP, Berrigan D, Dodd KW, Masse LC, Tilert T, Mc-
Schuch FB, Vancampfort D, Sui X, Rosenbaum S, Firth J, Dowell M. 2008. Physical activity in the United States
Richards J, Ward PB, Stubbs B. 2016. Are lower levels of measured by accelerometer. Med Sci Sports Exerc 40:
cardiorespiratory fitness associated with incident depres- 181 –188.
sion? A systematic review of prospective cohort studies.
Prev Med 93: 159 –165. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalai-
nen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S,
Scott LJ, Erdos MR, Huyghe JR, Welch RP, Beck AT, Wol- Laakso M, Louheranta A, Rastas M, et al. 2001. Preven-
ford BN, Chines PS, Didion JP, Narisu N, Stringham
tion of type 2 diabetes mellitus by changes in lifestyle
HM, et al. 2016. The genetic regulatory signature of
among subjects with impaired glucose tolerance. N
type 2 diabetes in human skeletal muscle. Nat Commun
Engl J Med 344: 1343– 1350.
7: 11764.
Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer-Kris-
Coenen-Schimke JM, Nair KS. 2003. Impact of aerobic tensen J, Pedersen BK. 1994. Bicycle exercise enhances
exercise training on age-related changes in insulin sensi- plasma IL-6 but does not change IL-1a, IL-1b, IL-6, or
tivity and muscle oxidative capacity. Diabetes 52: 1888– TNF-a pre-mRNA in BMNC. J Appl Physiol (1985) 77:
1896. 93– 97.
Slentz CA, Aiken LB, Houmard JA, Bales CW, Johnson JL, van Praag H, Kempermann G, Gage FH. 1999. Running
Tanner CJ, Duscha BD, Kraus WE. 2005. Inactivity, exer- increases cell proliferation and neurogenesis in the adult
cise, and visceral fat. STRRIDE: A randomized, con- mouse dentate gyrus. Nat Neurosci 2: 266–270.
trolled study of exercise intensity and amount. J Appl Vaughan RA, Gannon NP, Barberena MA, Garcia-Smith R,
Physiol (1985) 99: 1613–1618. Bisoffi M, Mermier CM, Conn CA, Trujillo KA. 2014.
Slentz CA, Houmard JA, Kraus WE. 2007. Modest exercise Characterization of the metabolic effects of irisin on
www.perspectivesinmedicine.org

prevents the progressive disease associated with physical skeletal muscle in vitro. Diabetes Obes Metab 16:
inactivity. Exerc Sport Sci Rev 35: 18– 23. 711 –718.
Stanford KI, Goodyear LJ. 2014. Exercise and type 2 diabe- Warburton DE, Nicol CW, Bredin SS. 2006. Health bene-
tes: Molecular mechanisms regulating glucose uptake in fits of physical activity: The evidence. CMAJ 174: 801–
skeletal muscle. Adv Physiol Educ 38: 308– 314. 809.
Stephenson EJ, Smiles W, Hawley JA. 2014. The relationship Wasserman DH. 2009. Four grams of glucose. Am J Physiol
between exercise, nutrition and type 2 diabetes. Med Endocrinol Metab 296: E11–E21.
Sport Sci 60: 1– 10. Widenfalk J, Olson L, Thoren P. 1999. Deprived of habitual
Subbotina E, Sierra A, Zhu Z, Gao Z, Koganti SR, Reyes S, running, rats downregulate BDNF and TrkB messages in
Stepniak E, Walsh SA, Acevedo MR, Perez-Terzic CM, et the brain. Neurosci Res 34: 125–132.
al. 2015. Musclin is an activity-stimulated myokine that
Wong KE, Mikus CR, Slentz DH, Seiler SE, DeBalsi KL,
enhances physical endurance. Proc Natl Acad Sci 112:
Ilkayeva OR, Crain KI, Kinter MT, Kien CL, Stevens
16042–16047.
RD, et al. 2015. Muscle-specific overexpression of PGC-
Tian Q, Erickson KI, Simonsick EM, Aizenstein HJ, Glynn 1a does not augment metabolic improvements in re-
NW, Boudreau RM, Newman AB, Kritchevsky SB, Yaffe sponse to exercise and caloric restriction. Diabetes 64:
K, Harris TB, et al. 2014. Physical activity predicts mi- 1532–1543.
crostructural integrity in memory-related networks in
very old adults. J Gerontol A Biol Sci Med Sci 69: 1284– Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D,
1290. Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM.
2013. Exercise induces hippocampal BDNF through a
Timmons JA, Knudsen S, Rankinen T, Koch LG, Sarzynski
PGC-1a/FNDC5 pathway. Cell Metab 18: 649 –659.
M, Jensen T, Keller P, Scheele C, Vollaard NB, Nielsen S, et
al. 2010. Using molecular classification to predict gains in Zierath JR, Krook A, Wallberg-Henriksson H. 2000. Insulin
maximal aerobic capacity following endurance exercise action and insulin resistance in human skeletal muscle.
training in humans. J Appl Physiol (1985) 108: 1487– Diabetologia 43: 821– 835.
1496. Zlebnik NE, Anker JJ, Carroll ME. 2012. Exercise to re-
Toedebusch RG, Ruegsegger GN, Braselton JF, Heese AJ, duce the escalation of cocaine self-administration in
Hofheins JC, Childs TE, Thyfault JP, Booth FW. 2016. adolescent and adult rats. Psychopharmacology 224:
AMPK agonist AICAR delays the initial decline in life- 387 –400.

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