cshperspectmed-BEX-a029694 1.perspectivesinmedicine.cshlp.org › content › 8 › 7 › a029694.full.pdfTitle: cshperspectmed-BEX-a029694 1..15 Created Date: 6/21/2018 8:40:04 AM

Health Benefits of Exercise

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

1Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 652112Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 652113Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri 652114Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211

Correspondence: [email protected]

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 themolecular mechanisms by which exercise sustains and improves quality of life. The currentreview begins with two short considerations. The first short presentation concerns the effectsof endurance exercise training on cardiovascular fitness, and how it relates to improvedhealth outcomes. The second short section contemplates emerging molecular connectionsfrom endurance training to mental health. Finally, approximately half of the remainingreview 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-ic interactions within cells, tissues/organs, systems, with remarkable cross talk occurringamong the former list.

The aim of this introduction is briefly todocument facts that health benefits of phys-ical activity predate its readers. In the 5th cen-tury BC, the ancient physician Hippocrates stat-ed: “All parts of the body, if used in moderationand exercised in labors to which each is accus-tomed, become thereby healthy and well devel-oped and age slowly; but if they are unused andleft idle, they become liable to disease, defectivein growth and age quickly.” However, by the 21stcentury, the belief in the value of exercise forhealth has faded so considerably, the lack ofexercise now presents a major public healthproblem (Fig. 1) (Booth et al. 2012). Similarly,the lack of exercise was classified as an actual

cause of chronic diseases and death (Mokdadet al. 2004).

Published in 1953, Jeremy N. Morris andcolleagues conducted the first rigorous epide-miological study investigating physical activityand chronic disease risk, in which coronaryheart disease (CHD) rates were increased inphysically inactive bus drivers versus active con-ductors (Morris et al. 1953). Since this pioneer-ing report, a plethora of evidence shows thatphysical inactivity is associated with the devel-opment of 40 chronic diseases (Table 1), includ-ing major noncommunicable diseases such astype 2 diabetes (T2D) and CHD, and as prema-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.a029694Cite this article as Cold Spring Harb Perspect Med 2018;8:a029694

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In this review, we highlight the far-reachinghealth benefits of physical activity. However,note that the studies cited here represent only afraction of the .100,000 studies showing posi-tive associations between the terms “exercise”and “health.” In addition, we discuss how exercisepromotes complex integrative responses thatlead to multisystem responses to exercise, an un-derappreciated area of medical research. Finally,we consider how strategies that “mimic” parts ofexercise training compare with physical exercisefor their potential to combat metabolic disease.

EXERCISE IMPROVES CARDIORESPIRATORYFITNESS

There is arguably no measure more importantfor health than cardiorespiratory fitness (CRF)

(commonly measured by maximal oxygen up-take, VO2max) (Blair et al. 1989). For example,Myers et al. (2002) showed that each 1 metabol-ic equivalent (1 MET) increase in exercise-testperformance conferred a 12% improvement insurvival, stating that “VO2max is a more power-ful predictor of mortality among men than oth-er established risk factors for cardiovascular dis-ease (CVD).” Low CRF is also well established asan independent risk factor of T2D (Booth et al.2002) and CVD morbidity and mortality (Ko-dama et al. 2009; Gupta et al. 2011). Similarly,Kokkinos et al. (2010) reported that men whotransitioned from having low to high CRF de-creased their mortality risk by �50% over an 8-yr period, whereas men who transitioned fromhaving high to low CRF increased their mortal-ity risk by �50%.

Prevention/treatmentPhysical activity

Cause of diseasePhysical inactivity

ModulatorsAge, diet,

gender,

genetics, etc.

Disease risk factorsDyslipidemia, hypertension,

hyperglycemia, visceral obesity, chronic

proinflammation, insulin resistance

Chronic diseaseType 2 diabetes, cardiovascular

disease, etc.

Reduced quality of life, premature death

Figure 1. Simplistic overview of how physical activity can prevent the development of type 2 diabetes and one ofits complications, cardiovascular disease. Physical inactivity is an actual cause of type 2 diabetes, cardiovasculardisease, 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 prematuredeath. However, physical activity can prevent and, in some cases, treat disease progression associated withphysical inactivity and other genetic and environmental factors.

G.N. Ruegsegger and F.W. Booth

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Importantly then, from the above para-graph, physical activity and inactivity are majorenvironmental modulators of CRF, increasingand decreasing it, respectively, often throughindependent pathways. Findings from rats se-

lectively bred for high or low intrinsic aerobiccapacity show that rats bred for high capacity,which are also more physically active, have28%–42% increases in life span compared tolow-capacity rats (Koch et al. 2011). Enduranceexercise is well recognized to improve CRF andcardiometabolic risk factors. Exercise improvesnumerous factors speculated to limit VO2maxincluding, but not restricted to, the capacity totransport oxygen (e.g., cardiac output), oxygendiffusion to working muscles (e.g., capillarydensity, membrane permeability, muscle myo-globin content), and adenosine triphosphate(ATP) generation (e.g., mitochondrial density,protein concentrations).

Data from the HERITAGE Family Study hasprovided some of the first knowledge of genesassociated with VO2max plasticity because of en-durance-exercise training. Following 6 wk of cy-cling training at 70% of pretraining VO2max,Timmons et al. (2010) performed messengerRNA (mRNA) expression microarray profilingto identify molecules potentially predictingVO2max training responses, and then assessedthese molecular predictors to determine wheth-er DNA variants in these genes correlated withVO2max training responses. This approachidentified 29 mRNAs in skeletal muscle and11 single-nucleotide polymorphisms (SNPs)that predicted �50% and �23%, respectively,of the variability in VO2max plasticity followingaerobic training (Timmons et al. 2010). Intrigu-ingly, pretraining levels of these mRNAs weregreater in subjects that achieved greater in-creases in VO2max following aerobic training,and of the 29 mRNAs, .90% were unchangedwith aerobic training, suggesting that alternativeexercise intervention paradigms or pharmaco-logical strategies may be needed to improveVO2max in individuals with a low responder pro-file for the identified predictor genes (Timmonset al. 2010). Keller et al. (2011) found that, inresponse to endurance training, improvementsin VO2max were associated with effectively up-regulating proangiogenic gene networks andmiRNAs influencing the transcription factor–directed networks for runt-related transcriptionfactor 1 (RUNX1), paired box gene 3 (PAC3),and sex-determining region Y box 9 (SOX9).

Table 1. Worsening of 40 conditions caused by thelack of physical activity with growth, maturation,and aging throughout life span

1. Accelerated biological aging/premature death2. Aerobic (cardiorespiratory) fitness (VO2max)3. Arterial dyslipidemia4. Balance5. Bone fracture/falls6. Breast cancer7. Cognitive dysfunction8. Colon cancer9. Congestive heart failure10. Constipation11. Coronary (ischemic) heart disease12. Deep vein thrombosis13. Depression and anxiety14. Diverticulitis15. Endometrial cancer16. Endothelial dysfunction17. Erectile dysfunction18. Gallbladder diseases19. Gestational diabetes20. Hemostasis21. Hypertension22. Immunity23. Insulin resistance24. Large arteries lose more compliance with aging25. Metabolic syndrome26. Nonalcoholic fatty liver disease27. Obesity28. Osteoarthritis29. Osteoporosis30. Ovarian cancer31. Pain32. Peripheral artery disease33. Preeclampsia34. Polycystic ovary syndrome35. Prediabetes36. Rheumatoid arthritis37. Sarcopenia38. Stroke39. Tendons being less stiff40. Type 2 diabetes

The breadth of the list implies that a single molecular

target will not substitute for appropriate daily physical

activity to prevent the loss of all listed items.


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Collectively, these results led the investigators tospeculate that improvements in skeletal muscleoxygen sensing and angiogenesis are primarydeterminates in training responses in VO2max(Keller et al. 2011).

Clinically important concepts have emergedfrom the pioneering HERITAGE Family Study.One new clinical concept is that a thresholddose–response relationship influences the per-centage of subjects responding with an increasein VO2max to endurance training volumes (withvolume being defined here as the product ofintensity � duration), as previously published(Slentz et al. 2005, 2007). Ross et al. (2015) laterextended the aforementioned Slentz et al. stud-ies. After a 24-wk-long endurance training study(Ross et al. 2015), percentages of women andmen identified as nonresponders to the training(i.e., defined as not increasing their VO2peak)progressively fell inversely to a two stepwise pro-gressive increase in endurance-exercise trainingvolume, as described next. Thirty-nine percent(15 of 39) of training subjects did not increasetheir VO2peak in response to the low-amount,low-intensity training; 18% (9 of 51) had noincrease in VO2peak in the group having high-amount, low-intensity training; and 0% (0 of31) who underwent high-amount, high-inten-sity training did not increase their VO2peak. Abiological basis for the dose–response rela-tionship in the previous sentence could bemade from an analysis of interval training (IT)and IT/continuous-training studies publishedfrom 1965 to 2012 (Bacon et al. 2013). A secondolder concept is being reinvigorated; Bacon et al.(2013) indicate that different endurance-exer-cise intensities and durations are needed for dif-ferent systems in the body. They suggest thatvery short periods of high-intensity endur-ance-type exercise may be needed to reach athreshold for peripheral metabolic adaptations,but that longer training durations at lower in-tensities are required to see large changes inmaximal cardiac output and VO2max.

A comparable example exists for resistancetraining. Maximal resistance loads require aminimum of 2 min/per wk for each musclegroup recruited by a specific maneuver to ob-tain a strength training adaptation [(8 contrac-

tions/set � 2 sec/contraction � 3 sets/day)� 2 days/wk) ¼ 96 sec]. As of 2016, one opin-ion from Sarzynski et al. (2016) for the molec-ular mechanisms by which endurance exercisedrives VO2max include, but are not limited to,calcium signaling, energy sensing and parti-tioning, mitochondrial biogenesis, angiogene-sis, immune functions, and regulation of au-tophagy and apoptosis.

Perhaps more importantly, lifelong aerobicexercise training preserves VO2max into old age.CRF generally increases until early adulthood,then declines the remainder of life in sedentaryhumans (Astrand 1956). The age-related de-cline in VO2max is not trivial, as Schneider(2013) reported a �40% decline in healthymales and females spanning from 20 to 70 yrof age. However, cross-sectional data showthat with lifelong aerobic exercise training,trained individuals often have the same VO2maxas a sedentary individual four decades younger(Booth et al. 2012). Myers et al. (2002) foundthat low estimated VO2max increases mortality4.5-fold compared to high estimated VO2max.They concluded, “Exercise capacity is a morepowerful predictor of mortality among menthan other established risk factors for cardiovas-cular disease.” Given the strong association be-tween CRF, chronic disease, and mortality, wefeel identifying the molecular transducers thatcause age-related reductions in CRF may haveprofound implications for improving healthspan and delaying the onset of chronic disease.In two of our recent papers, transcriptomics wasperformed on the triceps muscle (Toedebuschet al. 2016) and on the cardiac left ventricle(Ruegsegger et al. 2017). We were addressingthe question of what molecule initiates the be-ginning of the lifelong decline in aerobic capac-ity with aging. Aerobic capacity (VO2max) in-volves, at a minimum, the next systems/tissues, as oxygen travels through the mouth,airways, pulmonary membrane, pulmonary cir-culation, left heart, aorta/arteries/capillaries,and sarcoplasm/myoglobin to mitochondria.We allowed female rats access, or no access, torunning wheels from 5 to 27 wk of age. Surpris-ingly, voluntary running had no effect on thedelay in the beginning of the lifetime decrease in



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VO2max. Our skeletal muscle transcriptomicselicited no molecular targets, whereas gene net-works suggestive of influencing maximal strokevolume were identified in the left ventricle tran-scriptomics (Ruegsegger et al. 2017).

Publications concerning the effects of exer-cise on the brain (from 54 to 216 papers listedon PubMed from 2007 to 2016) have increased400%. In addition, a 2016 study (Schuch et al.2016) of three previous papers reported thathumans with low- and moderate-CRF had76% and 23%, respectively, increased risk ofdeveloping depression compared to high CRFin three publications. With this forming trend,the next section will consider exercise and brainhealth.

EXERCISE IMPROVES MENTAL HEALTH

Many studies support physical activity as a non-invasive therapy for mental health improve-ments in cognition (Beier et al. 2014; Bielak etal. 2014; Tian et al. 2014), depression (Kratz etal. 2014; McKercher et al. 2014; Mura et al.2014), anxiety (Greenwood et al. 2012; Nishi-jima et al. 2013; Schoenfeld et al. 2013), neuro-degenerative diseases (i.e., Alzheimer’s and Par-kinson’s disease) (Bjerring and Arendt-Nielsen1990; Mattson 2014), and drug addiction (Zleb-nik et al. 2012; Lynch et al. 2013; Peterson et al.2014). In 1999, van Praag et al. (1999) showedthe survival of newborn cells in the adult mousedentate gyrus, a hippocampal region importantfor spatial recognition, is enhanced by volun-tary wheel running. Similarly, spatial patternseparation and neurogenesis in the dentate gy-rus are strongly correlated in 3-mo-old micefollowing 10 wk of voluntary wheel running(Creer et al. 2010), and the development of newneurons in the dentate gyrus is coupled with theformation of new blood vessels (Pereira et al.2007). Many exercise-related improvements incognitive function have been associated withlocal and systemic expression of growth factorsin the hippocampus, notably, brain-derivedneurotrophic factor (BDNF) (Neeper et al.1995; Cotman and Berchtold 2002). BDNF pro-motes many developmental functions in thebrain, including neuronal cell survival, differen-

tiation, migration, dendritic arborization, andsynaptic plasticity (Park and Poo 2013). In rathippocampus, regular exercise promotes a pro-gressive increase in BDNF protein for up to atleast 3 mo (Berchtold et al. 2005). In an oppositemanner, BDNF mRNA in the hippocampus israpidly decreased by the cessation of wheel run-ning, suggesting BDNF expression is tightly re-lated to exercise volume (Widenfalk et al. 1999).

Findings by Wrann et al. (2013) highlightone mechanism by which endurance exercisemay up-regulate BDNF expression. To summa-rize, Wrann et al. (2013) noted that exerciseincreases the activity of the estrogen-relatedreceptor a (ERRa)/peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a)complex, in turn increasing levels of the exer-cise-secreted factor FNDC5 in skeletal muscleand the hippocampus, whose cleavage productsprovide beneficial effects in the hippocampusby increasing BDNF gene expression. While fu-ture research should determine whether theFNDC5 cleavage-product was produced locallyin hippocampal neurons or was secreted intothe circulation, this finding eloquently displaysone mechanism responsible for brain healthbenefits following exercise. Similarly, work byvan Praag and colleagues suggests that exerciseor pharmacological activation of AMP-activat-ed protein kinase (AMPK) in skeletal muscleenhances indices of learning and memory, neu-rogenesis, and gene expression related to mito-chondrial function in the hippocampus (Kobiloet al. 2011, 2014; Guerrieri and van Praag 2015).

Insulin-like growth factor 1 (IGF-1), is cen-tral to many exercise-induced adaptations in thebrain. Like BDNF, physical activity increases cir-culatory IGF-1 levels and both exercise and in-fusion of IGF-1 increase BrdUþ cell number andsurvivability in the hippocampus (Trejo et al.2001). Similarly, the protective effects of exer-cise on various brain lesions are nullified byanti-IGF-1 antibody (Carro et al. 2001).

In 1979, Greist et al. (1979) provided evi-dence that running reduced depression symp-toms similarly to psychotherapy. However, theprecise mechanisms by which exercise preventsand/or treats depression remain largely un-known. Of the proposed mechanisms, increases



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in the availability of brain neurotransmittersand neurotrophic factors (e.g., BDNF, dopa-mine, glutamate, norepinephrine, serotonin)are perhaps the best studied. For example, tyro-sine hydroxylase (TH) activity, the rate-limitingenzyme in dopamine formation, in the stria-tum, an area of the brain’s reward system, isincreased following 7 days of treadmill runningin an intensity-dependent manner (Hattoriet al. 1994). Voluntary wheel running is alsohighly rewarding in rats, and voluntary wheelrunning in rats lowers the motivation to self-administer cocaine, suggesting exercise may bea viable strategy in the fight against drug addic-tion (Larson and Carroll 2005).

Similar to the above examples, secreted fac-tors from skeletal muscle have been linked to theregulation of depression. Agudelo et al. (2014)showed that exercise training in mice and hu-mans, and overexpression of skeletal musclePGC-1a1, leads to robust increases in kynure-nine amino transferase (KAT) expression inskeletal muscle, an enzyme whose activity pro-tects from stress-induced increases in depres-sion in the brain by converting kynurenineinto kynurenic acid. Additionally, overexpres-sion of PGC-1a1 in skeletal muscle left miceresistant to stress, as evaluated by various behav-ioral assays indicative of depression (Agudeloet al. 2014). Simultaneously, they report geneexpression related to synaptic plasticity in thehippocampus, such as BDNF and CamkII, wereunaffected by chronic mild stress compared towild-type mice. Collectively, these findings sug-gest exercise-induced increases in skeletal mus-cle PGC-1a1 may be an important regulator ofKAT expression in skeletal muscle, which, viamodulation in plasma kynurenine levels, mayalleviate stress-induced depression and pro-mote hippocampal neuronal plasticity.

TYPE 2 DIABETES, MITOCHONDRIA,AND EXERCISE

T2D Predictions Show a Pandemic

In a 2001 Diabetes Care article (Boyle et al.2001), investigators at the U.S. Centers for Dis-ease Control (CDC) predicted 29 million U.S.

cases of T2D would be present in 2050. Unfor-tunately, the 2001 prediction of 29 million wasreached in 2012! For 2012, the American Dia-betes Association reported that 29 millionAmericans had diagnosed and undiagnosedT2D, which was 9% of the American population(Dwyer-Lindgren et al. 2016). More rapid in-creases in T2D are now predicted by the CDCthan in the previous estimate. The CDC nowpredicts a doubling or tripling in T2D in 2050.The tripling would mean that one out of threeU.S. adults would have T2D in their lifetime by2050 (Boyle et al. 2010), which would be .100million U.S. cases. The International DiabetesFederation (IDF) reports T2D cases worldwide.In 2015, the IDF reported that 344 and 416 mil-lion North American (including Caribbean)and worldwide adults, respectively, had T2D.Furthermore, the IDF predicts for 2040 that413 and 642 million, respectively, will haveT2D. In sum, T2D is now pandemic, and thepandemic will increase in numbers without cur-rent apparent action within the general public.

Type 2 Diabetes Prevalence Is Based on aStrong Genetic Predisposition

The Framingham study found that T2D risk inoffspring was 3.5-fold and sixfold higher for asingle and two diabetic parent(s), respectively,as compared to nondiabetic offspring (Meigset al. 2000). Thus, T2D is gene-based.

Noncoding regions of the human genomecontain .90% of the .100 variants associatedwith both T2D and related traits that were ob-served in genome-wide association studies(Scott et al. 2016). Another 2016 paper (Kwakand Park 2016) lists at least 75 independent ge-netic loci that are associated with T2D. Takentogether, T2D is a complex genetic disease (Scottet al. 2016).

Type 2 Diabetes Is Modulated by Lifestyle,with Exercise as the More Powerful LifestyleFactor

Three large-scale epidemiological studies havebeen performed on prediabetics, each in a dif-ferent geographical location. The first study,



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and only study to have separate study arms fordiet and exercise, was in China. The pure exer-cise intervention group had a 46% reduction inthe onset of T2D, relative to the nontreatedgroup, after 6 yr of the study (Pan et al. 1997).Diet alone reduced T2D by 31% in the Chinesestudy. The second study on T2D was the FinnishDiabetes Prevention Study. It found a 58% re-duction in T2D in the lifestyle intervention(combined diet and exercise) in its 522 predia-betic subjects after a mean study duration of3.2 yr (Tuomilehto et al. 2001). The latest ofthe three studies was in the U.S. Diabetes Pre-vention Program. The large randomized trial (n¼ 3150 prediabetics) was stopped after 2.8 yr,because of harm to the control group. T2Dprevalence in the high-risk adults was reducedby 58% with intensive lifestyle (diet and exer-cise) intervention, whereas the drug arm (met-formin) of the study only reduced T2D by 31%,both compared to the noninnervation group(Knowler et al. 2002). Thus, if differences ingenetics in the above three differing ethnicitiesare not a factor, combined exercise and diet re-main more effective in T2D prevention than thedrug metformin two decades ago.

Exercise Increases Glucose by SignalingIndependent of the Insulin Receptor

A single exercise bout increases glucose uptakeby skeletal muscle, sidestepping the insulin re-ceptor and thus insulin resistance in T2D pa-tients (Holloszy and Narahara 1965; Goodyearand Kahn 1998; Holloszy 2005). After insulinbinding to its receptor, insulin initiates a down-stream signaling cascade of tyrosine autophos-phorylation of insulin receptor, insulin receptorsubstrate 1 (IRS-1) binding and phosphoryla-tion, activation of a PI3K-dependent pathway,including key downstream regulators proteinkinase B (Akt) and the Akt substrate of160 kDa (AS160), ultimately promoting glu-cose transporter 4 (GLUT4) translocation tothe plasma membrane (Rockl et al. 2008; Stan-ford and Goodyear 2014). Despite normalGLUT4 levels, insulin fails to induce GLUT4translocation in T2D (Zierath et al. 2000). How-ever, exercise activates a downstream insulin-

signaling pathway at AS160 and TBC1 domainfamily member 1 (TBC1D1) (Deshmukh et al.2006; Maarbjerg et al. 2011), facilitating GLUT4expression translocation to the plasma mem-brane independent of the insulin receptor. Wecontend that exercise could be considered as avery powerful tool to primarily attenuate theT2D pandemic.

Complex Biology of T2D Interactions with theComplex Biology of Exercise

An important consideration from the above isthat T2D is such a genetically complex diseasethat a single gene has not been proven to besufficiently causal to be effective, at this stagein time, to be a successful target for pharmaco-logical treatment. The expectation for a singlemolecule target has been met for infectious dis-eases, which are often monogenic diseases. Forexample, a vaccine against smallpox was highlysuccessful. Edward Jenner in 1796 producedthe first successful vaccine. An important factis that exercise is genetically complex. Theliterature allows us to speculate that exercise isat least as genetically complex as the approxi-mately 75 genes associated with T2D (Kwakand Park 2016). An example indicating that ex-ercise is complex biology follows. RNA sequenc-ing analysis of all 119 vastus lateralis musclebiopsies found that endurance training for 4days/wk for 12 wk produced the differential ex-pression of 3404 putative isoforms, belonging to2624 different genes, many associated with oxi-dative ATP production in 23 women and menaged 29 yr old (Lindholm et al. 2016). Our no-tion is that over 2600 genes suggests complexbiology.

A “Case-Type” Study of the MolecularUnderpinnings of Exercise, Mitochondria,and T2D Interactions

A PubMed search for the terms “diabetes mito-chondria exercise molecular” elicited 74 papers.We arbitrarily selected some of the most recent50 (spanning from mid-2014 into January2017), with the assumption they would be rep-resentative of any other papers that we did not



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find in our search. Papers fell into our two ar-bitrary categories of single gene studies versus“omic”-type studies. First, subcategories ofstudies that develop themes will be arbitrarilypresented.

Recent Studies Show Single GeneManipulation Alters Mitochondrial Leveland Running Performance

Numerous reports in the past couple of yearsobserved that single gene manipulations in-crease mitochondrial gene expression and activ-ity, which was also associated with increasedexercise performance/capacity. A few of theseare presented below:

1. Irisin was shown to increase oxidative me-tabolism in myocytes and increase PGC-1amRNA and protein (Vaughan et al. 2014),which extends the first observation madeearlier in adipose tissue by Spiegelman (Bos-trom et al. 2012).

2. Patients with impaired glucose toleranceunderwent low-intensity exercise training.Patients whose mitochondrial markers in-creased to levels that were measured in a sep-arate cohort of nonexercised healthy individ-uals recovered normal glucose tolerance(Osler et al. 2015). In opposition, those pa-tients whose mitochondria markers did notimprove, remained with impaired glucosetolerance.

3. In 2003, muscle PGC-1a mRNA was shownto be induced by endurance-exercise trainingin human skeletal muscle (Short et al. 2003).PGC-1a was shown to have multiple iso-forms (Lin et al. 2002). After a 60-min cy-cling bout, human vastus lateralis biopsieswere taken from both sexes in their mid-20s. Additional biopsies were taken 30 min,and at 2, 6, and 24 hr postexercise. At 30 minpostexercise, PGC-1a-ex1b mRNA andPGC-1a mRNA increased 468- and 2.4-fold, respectively, whereas PGC-1a-ex1bprotein and PGC-1a protein increased 3.1-fold and no change, respectively. Gidlundet al. (2015) interprets the above data as im-plying PGC-1a-ex1b could be responsible

for other changes that have previously beenrecorded before the increase in total PGC-1apostexercise.

4. Mice with knockout of the kinin B1 receptorgene had higher mitochondrial DNA quan-tification and of mRNA levels of genes relat-ed to mitochondrial biogenesis in soleus andgastrocnemius muscles and had higher exer-cise times to exhaustion, but did not havehigher VO2max (Reis et al. 2015).

5. Mice do not normally express cholesteryl es-ter transfer protein (CETP), which is a lipidtransfer protein that shuttles lipids betweenserum lipoproteins and tissues. Overex-pression of CETP in mice after 6 wk on ahigh-fat diet increased treadmill running du-ration and distance, mitochondrial oxidationof glutamate/malate, but not palmitoyl-carnitine oxidation, and doubled PGC-1amRNA concentration (Cappel et al. 2015).

6. The myokine musclin is a peptide secretedfrom exercising muscle during treadmillrunning. Removal of musclin release duringrunning results in lowered VO2max, lowerskeletal muscle mitochondrial content andrespiratory complex protein expression,and reduced exercise tolerance (Subbotinaet al. 2015).

7. Lactate dehydrogenase B (LDHB), whichproduces pyruvate from lactate, was overex-pressed in mouse skeletal muscle. Increasesin markers of skeletal muscle mitochondriawere associated with increased running dis-tance in a progressive speed test, and in-creased peak VO2 (Liang et al. 2016).

8. Another example of endurance-type exerciseadaptations is the 2016 paper that transcrip-tion factor EB (TFEB) regulates metabolicflexibility in skeletal muscle independent ofPGC-1a during endurance-type exercise(Mansueto et al. 2017). Lack of metabolicflexibility, termed “metabolic inflexibility,”is important because it is common in T2D.One definition of metabolic inflexibility is itsinability to rapidly switch between glucoseand fatty acid substrates for ATP production



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when nutrient availability changes from highblood glucose levels immediately after a mealto decreasing below 100 mg/dl when noteating for hours after a meal. A clinicalconsequence of T2D-induced metabolic in-flexibility is prolonged periods of hypergly-cemia, because skeletal muscle is more insu-lin insensitive in T2D. In contrast, aftersufficient endurance exercise, skeletal muscleincreases its insulin sensitivity by a secondpathway that is independent of proximalpostreceptor insulin signaling (see Stephen-son et al. 2014 for further discussion).

Studies Showing that Manipulation of OneSignaling Molecule Does Not Alter Expressionof All Genes with Mitochondrial FunctionsFound in Skeletal Muscles of Wild-TypeAnimals to Exercise Training

A 2010 review article (Lira et al. 2010) concludesfrom gene-deletion studies that p38g MAPK/PGC-1a signaling controls mitochondrial bio-genesis’ adaptation to endurance exercise inskeletal muscle. Two studies do not completelyagree with the conclusion in the review article.The Pilegaard laboratory published a 2008study (Leick et al. 2008) that did not confirmtheir hypothesis that PGC-1a was required forevery metabolic protein adaptive increase afterendurance-exercise training by skeletal muscle.They reported that PGC-1a was not requiredfor endurance-training-induced increases inALAS1, COXI, and cytochrome c expression(Leick et al. 2008). Their interpretation, at thattime, was that molecules other than PGC-1acan exert exercise-induced mitochondrial adap-tations. A second study published in 2012 ren-dered a similar verdict. A 12-day program ofendurance training led to the middle portionof the gastrocnemius muscle demonstrating asimilar 60% increase in mitochondrial densityin both wild-type and PGC-1a muscle-specificknockout mice (Myo-PGC-1aKO) (Rowe et al.2012). The paper concludes that PGC-1a is dis-pensable for endurance-exercise’s induction ofskeletal muscle mitochondrial adaptations.

Exercise signaling targets have actions thatare independent of PGC-1a, which is specific

to endurance exercise. In 2002, two groups iden-tified PGC-1b, a transcriptional coactivatorclosely related to PGC-1a (Kressler et al. 2002;Lin et al. 2002). Later in 2012, the PGC-1a4variant of PGC-1awas found to induce skeletalmuscle hypertrophy and strength (Ruas et al.2012). The importance of the finding of aPGC-1a variant is that it partially explains thephenotypic variation for differing types of exer-cise. Since the 1970s (Holloszy and Booth 1976),it has been appreciated that the biochemical andanatomical observations between enduranceand resistance differed. For example, Holloszyand Booth (1976) noted in 1976 that, whereasendurance-type exercise markedly increasedskeletal muscle mitochondrial density withvery minor increases in muscle fiber diameter,strength-type exercise, in contrast, increasedmuscle fiber diameter without increases in skel-etal muscle mitochondrial density. Taken to-gether, a drug specific for PGC-1awill not likelymimic separate physical training for endurance,strength/resistance, and coordination types ofexercise in the same subject. Thus, the commonusage of the term exercise capacity is a misnomerbecause endurance training and resistance train-ing were shown to have different exercise capac-ity phenotypes very long ago.

In a 2015 Diabetes paper (Wong et al. 2015),Muoio’s laboratory concluded that changes inglucose tolerance and total body fat dependedupon how much energy is expended in con-tracting muscle rather than muscle mitochon-drial content or substrate selection. A finding tosupport the previous sentence was the glucosetolerance tests (GTTs). MCK-PGC-1amice andtheir nontransgenic (NT) littermates were notdifferent in GTT, with both being the most glu-cose intolerant after 10 wk of high-fat feeding.Adding 10 wk of voluntary wheel running tothe two high-fat-feed groups during the next10-wk period (weeks 11–20 of the experiment)lowered the glucose intolerance, and then dur-ing weeks 21–30 of the experiment, glucose in-tolerance was further lowered by adding 25%caloric restriction with the high-fat food andrunning during the final 10 wk. The percentageweight lost after 30 wk of high-fat feeding waspositively related to greater running distances.



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No single front-runner gene candidate couldbe identified by principle component analysis.Taken together, the paper suggests “doubts” thatpharmacological exercise mimetics that increasemuscle oxidative capacity will be effectiveantiobesity and/or antidiabetic agents. Rather,Muoio and investigators suggest energy expen-diture by muscle contraction induces localizedshifts in energy balance inside the muscle fiber,which then initiates a broad network of meta-bolic intermediates regulating nutrient sensingand insulin action. A further discussion ofcomplex biology produced by polygenicity con-tinues next.

POLYGENICITY OF EXERCISE LEADSTO COMPLEX MULTISYSTEM RESPONSESTO IMPROVE HEALTH OUTCOMES

Multiples tissues, organs, and systems are influ-enced by physical activity, or the lack thereof(Table 2).

To present one extreme, that most willagree, one molecule will not describe the1000s of molecules adapting to aerobic, resis-tance, and coordination exercise training. Onthe opposite extreme, many could likely agreethat usage of the various “omics” underlying alladaptations to physical activity will differ (i.e.,not be identical in most aspects) among thenext list: various cell types within a tissue/or-gan, tissues/organs, and various intensities ofphysical activity (i.e., the thresholds amonggene responses for health benefits will differbecause of the presence of responders and non-responders, or protein isoform type); duringvarious types cycling (circadian or menstrual);postprandial versus fasting between meals; maleand female; child, adult, and the elderly; trainedand untrained; aerobic- and resistance-exercisetypes; and so forth. Others have repetitivelywritten that only �59% of the risk reductionfor all forms of CVD have been shown to becaused by effects through traditional factors(Mora et al. 2007; Joyner and Green 2009).Thus, we pose the next question: what is theidentity of all molecules in the yet-to-be-discov-ered gap between our knowledge of single genefunctions and the totality of personalized pre-scription of physical activity to maximize theperiod of life free of any chronic disease, termedhealth span?

While approaches using single-gene manip-ulations are valuable tools, research must alsofocus on integrating exercise-responsive mole-cules into networks that maintain or improvehealth. This process will reveal complex, multi-system, polygenic networking essential for theadvancement of many goals pertaining to exer-cise physiology, such as tailoring exercise pre-scriptions and implementing personalizedmedicine. One example is the developing myo-kine network with auto-, para-, and endocrinemolecules. The first myokine interleukin (IL)-6began to be described as early as 1994 by thePedersen laboratory (Ullum et al. 1994), with ahistory of its development as the first exercisemyokine recounted in 2007 (Pedersen et al.2007). Since their discovery, myokine actionwithin and at a distance from their origins inskeletal muscle have been increasingly studied,

Table 2. Worsening of maximal functioning in select-ed major organ/tissue/systems that are caused by thelack of physical activity with growth, maturation, andaging

Site

Organ/tissue/system loses

designated function, most with

aging after maturation

Brain Specific types of cognitionBrain Motor coordination and balanceHeart Maximal pumping volume/

minutePeripheral

circulationMaximal capacity to supply blood

to working musclesPeripheral

circulationPrevention of capillary rarefaction

in feetSkeletal muscle Less mass and strengthSkeletal muscle Lower insulin sensitivityPancreas Loss of b cellsAerobic capacity LowerBone Less mass and strengthLiver Excessive fat storage

The higher their maximal function is before the end of

each item’s maturation, the longer chances are that the

quality of life will remain optimal. The breadth of the list

implies that a single molecular target will not substitute for

appropriate daily physical activity to prevent the loss of all

listed items.



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as schematically illustrated by Schnyder andHandschin (2015) (Fig. 2).

Similarly, maximal aerobic exercise is ac-companied by tremendous stress on manysystems, yet whole-body homeostasis is remark-ably maintained. For example, world-class en-durance athletes can increase whole-body ener-gy production well over 20-fold (Joyner andCoyle 2008), whereas maintaining blood glu-cose concentrations at resting levels (Wasser-man 2009). Intuitively, such effort would re-quire sophisticated interorgan cross talk andpolygenic integration of numerous functions.

Exercise Provides Too Many Benefits to “Fitinto a Single Pill”

Despite the well-known benefits of exercise,most adults and many children lead relativelysedentary lifestyles and are not active enoughto achieve the health benefits of exercise (War-burton et al. 2006; Fried 2016). Accelerometrymeasurements suggest that .90% of U.S. indi-viduals .12 yr of age and �50% of childrenaged 6–11 yr old fail to meet U.S. Federal phys-ical activity guidelines (Troiano et al. 2008).Given this incredibly low compliance, the iden-

Bone

CNTF: inhibits osteoblasts

OSM: inhibits mammary cancer cell growth

IL-6: increased GLP1 secretion

IL-6: increased GLP1 secretionSPARC: suppressed colon tumorigenesis

IL-15: increased thermogenesis and β-oxidation

IL-6: increased lipolysisFGF21: increased glucose uptakeIrisin: increased thermogenic program, browningBAIBA: increased thermogenic program, browningMetrnl: increased thermogenic program, browning

BDNF: learning and memoryIrisin: increased hippocampal BDNF expression

Breast

Pancreas

Gut

Liver

WAT

BAT

Brain

IL-8: angiogenesisVEGF: angiogenesis

MSTN: negative regulator of muscle massIL-6: increased glucose uptake and β-oxidationIL-15: hypertrophyBDNF: increased β-oxidationIrisin: increased energy expenditure and oxidative metabolism

Bloodstream

Skeletal muscle

Myokines

Figure 2. Figure provides an illustration of myokine production by skeletal muscle for actions within or at adistance. 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 endothelialgrowth factor. (From Schnyder and Handschin 2015; reprinted, with permission, courtesy of PMC OpenAccess.)



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tification of genetic and/or orally active agentsthat mimic the effects of endurance exercisemight have high appeal for a majority of seden-tary individuals. This high appeal has led torecent identification/development of exercise“mimetics.” In 2009, we set criteria for properusage of the term “exercise mimetic,” basedupon its common usage (Booth and Laye2009). We gave the Oxford English Dictionary’sdefinition of mimetic, “A synthetic compoundthat produces the same (or a very similar) effectas another (especially a naturally occurring)compound.” While many exercise “mimetics”activate signaling pathways commonly associat-ed with muscle endurance, these agents have notcompletely mimicked all effects for all typesof exercise. For example, the AMPK activator5-aminoimidazole-4-carboxamide ribonucleo-tide (AICAR), when given daily to rats over a5-wk-period, did not increase maximal oxygenconsumption (VO2peak) in the sedentary groupof rats that were forced to run to VO2peak ontreadmills, as compared to sedentary rats receiv-ing the vehicle (Toedebusch et al. 2016). Thus, inour opinion, the published claim (Narkar et al.2008) that AICAR is an exercise mimetic is in-validated because it did not increase VO2peak.While these agents may undoubtedly havespecific health benefits, it is currently impracti-cal to assume that all of the benefits of exercisecan be replaced by “exercise mimetics.”

CONCLUDING REMARKS

Exercise is a powerful tool in the fight to preventand treat numerous chronic diseases (Table 1).Given its whole-body, health-promoting na-ture, the integrative responses to exercise shouldsurely attract a great detail of interest as the no-tion of “exercise is medicine” continues to itsintegration into clinical settings.

ACKNOWLEDGMENTS

The authors disclose no conflicts of inter-est. Partial funding for this project was ob-tained from grants awarded to G.N.R. (AHA16PRE2715005).

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15, 20172018; doi: 10.1101/cshperspect.a029694 originally published online MayCold Spring Harb Perspect Med

Gregory N. Ruegsegger and Frank W. Booth Health Benefits of Exercise

Subject Collection The Biology of Exercise

Adaptations to Endurance ExerciseExosomes as Mediators of the Systemic

Adeel Safdar and Mark A. Tarnopolsky

Effects of Exercise and Aging on Skeletal MuscleGiovanna Distefano and Bret H. Goodpaster

ChallengesAdvances, Current Knowledge, and FutureMuscle Mitochondrial Biogenesis: Historical Molecular Basis of Exercise-Induced Skeletal

Christopher G.R. Perry and John A. Hawley

Muscle-Adipose Tissue Cross TalkKristin I. Stanford and Laurie J. Goodyear

Exercise Metabolism: Fuels for the FireMark Hargreaves and Lawrence L. Spriet Specificity

Performance Fatigability: Mechanisms and Task

Sandra K. HunterHealth Benefits of Exercise

Gregory N. Ruegsegger and Frank W. BoothAdaptations to Endurance and Strength Training

David C. Hughes, Stian Ellefsen and Keith Baar

Fiber HypertrophyMolecular Regulation of Exercise-Induced Muscle

Gregory R. AdamsMarcas M. Bamman, Brandon M. Roberts and

The Bioenergetics of ExerciseP. Darrell Neufer

Responses to ExercisePhysiological Redundancy and the Integrative

Michael J. Joyner and Jerome A. DempseyStructure, and Health in HumansEffects of Exercise on Vascular Function,

Daniel J. Green and Kurt J. SmithOn the Run for Hippocampal Plasticity

PraagC'iana Cooper, Hyo Youl Moon and Henriette van Complex

Control of Muscle Metabolism by the Mediator

Bassel-DubyLeonela Amoasii, Eric N. Olson and Rhonda

Handling2+The Importance of Strictly Controlled Cellular CaMolecular Basis for Exercise-Induced Fatigue:

WesterbladArthur J. Cheng, Nicolas Place and Håkan

between Low Exercise Capacity and Disease RiskTheoretical and Biological Evaluation of the Link

Lauren Gerard Koch and Steven L. Britton

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved


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