Zhengtang Qi*，Shuzhe Ding*

aThe Key Laboratory of Adolescent Health Assessment and Exercise Intervention（East China Normal University），Ministry of Education，Shanghai 200241，ChinabSchool of Physical Education and Health，East China Normal University，Shanghai 200241，China Received 18 January 2016；revised 4 March 2016；accepted 27 March 2016 Available online 7 April 2016



Targeting mitochondrial phenotypes for non-communicable diseases

Zhengtang Qia，b，*，Shuzhe Dinga，b，*

aThe Key Laboratory of Adolescent Health Assessment and Exercise Intervention（East China Normal University），Ministry of Education，Shanghai 200241，ChinabSchool of Physical Education and Health，East China Normal University，Shanghai 200241，China Received 18 January 2016；revised 4 March 2016；accepted 27 March 2016 Available online 7 April 2016

Abstract

Theconceptthat“ExerciseisMedicine”hasbeenchallengedbytherisingprevalenceofnon-communicablechronicdiseases（NCDs）.Thisispartly due to the fact that the underlying mechanisms of how exercise influences energy homeostasis and counteracts high-fat diets and physical inactivity is complex and remains relatively poorly understood on a molecular level.In addition to genetic polymorphisms in humans that lead to gross variations inresponsivenesstoexercise，adaptationinmitochondrialnetworksiscentraltophysicalactivity，inactivity，anddiet.Toharnessthebenefitsofexercise forNCDs，muchworkstillneedstobedonetoimprovehealtheffectivelyonasocietallevelsuchasdevelopingpersonalizedexerciseinterventionsaided byadvancesinhigh-throughputgenomics，proteomics，andmetabolomics.Weproposethatunderstandingthemitochondrialphenotypeaccordingtothe molecular information of genotypes，lifestyles，and exercise responsiveness in individuals will optimize exercise effects for prevention of NCDs.

©2016 Production and hosting by Elsevier B.V.on behalf of Shanghai University of Sport.This is an open access article under the CC BY-NC-ND license（http://creativecommons.org/licenses/by-nc-nd/4.0/）.

Keywords:Energy metabolism；Exercise；Mitochondrial；Non-communicable chronic diseases；Physical activity；Precision medicine

1.Introduction

The slogan of“Exercise is Medicine”promotes a global movement to reduce sedentary lifestyles.“Exercise is Medicine”attempts to raise physical activity（PA）levels to a standard medicine for clinical practice，because the benefits of exercise are purported to reduce the risk of non-communicable chronic diseases（NCDs），such as cardiovascular disease，type 2 diabetes and certain cancers.However，in the past decades，the global morbidity and mortality of NCDs is increasing regardless of the efforts of World Health Organization and national governments to promote physically more active lifestyle.1

ThenumberofU.S.adultsdoingsufficientPAincreasedfrom 22%in 1996 to 51.6%in 2014.2In China，the number of adults attending PA also increased from 15.5%in 1996，to 28.2%in 2008，andto33.9%in2014.3Thereareremarkableachievements in promoting PA over the past decade in different countries. Nonetheless，it is discouraging that the mortality between ages 30 and 70 years due to NCDs increased in the US in 2000-2012 withNCDsaccountingfor88%oftotaldeathsin2014.InChina， NCDs also increased in males after 2004 and in females during 2000-2012；NCDsaccountfor87%oftotaldeathsin2014.4The metabolic risk factors for development of NCDs such as body mass index（BMI）and fasting blood glucose showed a less optimistic trend during 1980-2008.5These statistics might indicate that there is no an apparent relationship between PA and NCDs risks.Nonetheless，if increases in BMI are reciprocal to increases in PA，it is possible that any benefits of moderate exerciseareoffsetbyincreasedfoodconsumption.Inthisreview，we look into those confounding factors and the possible underlying mechanisms，which may have shaded the outcomes of health benefit of exercise from“Exercise is Medicine”.The precision medicine initiative launched by the US claims that detailed genetic and other molecular information about a patient’s disease will be routinely used to deploy effective，patient-specific remedies in future.6It is urgent to promote personalized exercise intervention linking curative exercise effects to specific health outcomes in different populations. Nonetheless，theweightingofgeneticandenvironmentalfactors contributing to exercise for health is poorly understood.

2.Energy balance challenged by unhealthy lifestyles

NCDs are often attributed to unhealthy diet and physical inactivity.Meanwhile，life expectancy is increasing with theability of modern societies to provide high-quality medical and socialfacilities，regardlessoftheseunhealthylifestyles.Tobetter evaluatetheextenttowhichPApreventsNCDs，themechanisms involving unhealthy lifestyles need to be explored at an evolutionaryandphysiologicallevel.Energybalanceiscriticalforthe survivalofallmammals.CurrentfindingssuggestthatNCDsare mostlyassociatedwithmetabolicdisorderanditscomplications. Metabolic syndrome is often characterized by higher BMI，hyperglycemia，hyperlipidemia，insulin resistance，ectopic lipid accumulation，and mitochondrial dysfunction，for example，in type 2 diabetes and cardiovascular diseases.7，8With these considerations，it is necessary to focus our attention on those lifestyles that probably impair energy balance.High-fat diets are a majorcontributortometabolicsyndrome.Physiologically，highfat diet leads to the impairment of fuel metabolism，increases in ectopic lipid accumulation in non-fat tissues（i.e.，muscle and liver）and consequent adiposity.Evolutionarily，humans have undergone a dramatic shift in the composition of diet and motivation to eat.9Currently people have more reasons to eat somethingcomparedtoourancestors，becausedietisanexpressionof culture and lifestyle，other than simply hunger.Unnecessary food intake overshoots the demand for energy and thereby impacts energy homeostasis.If excessive food consumption is the main reason for obesity，weight loss should be achieved by reducingfoodintakeandincreasingenergyexpenditurewithPA. However，a cohort study that took place from 2004 to 2014 showed that PA and diet control might be not as effective as expectedinobesitytreatment.Theauthorsrevealthattheannual probability of attaining normal weight was 1/210 for men and 1/124forwomenafterobesitytreatments.10Suchalowprobability is not encouraging for counteracting obesity through these means.It is noteworthy that the individual propensity to be physicallyactiveisdeterminedbybothgeneticandenvironmental factors.11The individual propensity to be obesity-prone or obesity-resistant in response to high-fat diet is，for example，associated with the acyl chain length of phosphocholine species，12hypothalamic-pituitary-thyroid axis function，13proteomic profile of adipose tissues and liver.14，15This indicates that the individual propensity for PA and diet needs to be taken into consideration in obesity treatment frameworks.

In direct contrast to PA，physical inactivity leads to the development of insulin resistance.16Bed rest reduced expression of PGC-1α and other genes involved in mitochondrial biogenesis，contributing to the developmentofinsulin resistance.17Evolutionarily，humans were selected to avoid extraneous PA because energy from food was limited and exercise increases unnecessary energy expenditure.Consequently，physical inactivity（except for necessary physical work）was the best strategy for survival when availability of food was limited.18Nonetheless，physical work in hunting for food coupled to lower energy intakes might have provided sufficient amount of PA to retain such a level of metabolic activity that our ancestors were resistant to NCDs.The advent of modern technology has now relegated PA from a necessity of human existence to lifestyle choice.Since physical inactivity poses a challenge to public health，exercise remains a most efficacious treatment for metabolic diseases，such as diabetes and cardiovascular diseases.Exercise provokes widespread perturbations in cells，tissues，and organs and challenges whole-body homeostasis by increasing metabolic activity of contracting skeletal muscles.19In doing so，exercise promotes “metabolic flexibility”—the ability to maintain metabolic health even in the face of excessive energy consumption.

Together，the metabolic syndrome appears to be at the intersection of endocrinology，oncology，and cardiology，such that maintaining energy balance has emerged as a major target for treating NCDs.Evolutionarily，the changes in food consumption and physical inactivity pose a great challenge to energy system in humans who have been evolutionally selected for food shortage and necessary physical work.Pathologically，long-term exposure to high-energy diet and physical inactivity induces obesity，insulin resistance and decreased energy expenditure.Although the synergistic interaction between unhealthy lifestyles and exercise remains elusive，PA is known as the best way to tame metabolic disorders and restore energy balance.

3.Mitochondria and metabolic health

Many NCDs involve mitochondrial dysfucntion.20While high-fat diets paradoxically result in an increase in mitochondrial biomass，they have also been associated with impaired mitochondrial respiratory capacity，mitochondrial biogenesis，insulin resistance，and metabolic inflexibility.21These same effects are related to physical inactivity.22By contrast，calorie restriction strengthens mitochondrial network and extends lifespan.23Exercise-induced mitochondrial biogenesis has been well documented，for example，in brain and skeletal muscle.24，25In these tissues mitochondrial plasticity follows the principle of“use it or lose it”；increased mitochondrial networks and mitochondrial function resulting from exercise are considered essential for health，while physical inactivity and sedentary behaviorsare associated with mitochondrialdispansion （Fig.1）.It is now evident that mitochondria function as important signaling organelles；for example，via releasing metabolites，reactive oxygen species，and peptides and ions.26The quantity of mitochondria in cells is controlled by the master regulator of mitochondrial biogenesis，PGC-1α signaling，and mitophagy pathways（mitochondrial breakdown）.We speculate that physical inactivity undermines the endo-symbiotic relationship between mitochondria and host eukaryotic cells.Here，we provide a framework by which mitochondria are provoked to drive the formation of the whole-cell phenotype（Fig.1）. Mechanistically，exercise has been proved to improve energy metabolism and mitochondrial adaptability.Thus，PA is a hopeful means to hold back the prevalence of NCDs.However，there is a great gulf between the bench and the bedside.A leading review indicates that a person’s predisposition to engage in exercise is highly variable and simultaneously influenced by the environment，complex genomics，and their interactions.27In short，exercise is not always effective for everyone at any time.The development of individualized exercise prescription for the control of NCDs is an appealing concept. Unhealthy lifestyles impair energy balance，mitochondrial adaptability，and mitochondrial-coupled cell signaling implicated in the pathogenesis of NCDs.Why is target-ing mitochondrial phenotype required for NCDs？In brief，the benefits of exercise to a person with NCDs are contingent on individual-level factors，such as lifestyles，environment，genotype，and so on.These factors，to a large extent，lead to the variability of mitochondrial phenotypes and affect a person’s responsiveness to exercise.Herein，we propose that targeting mitochondrial phenotypes will be a key necessity for treating NCDs（Fig.1）.

Fig.1.The 2-way adaptations of mitochondria and mitochondrial-coupled cell phenotype.Mitochondria are highly self-organized to adapt via up-or down-regulation in response to energy intake and expenditure，such as high-fat diets，calorie restriction，physical activity and inactivity.The mechanisms underlying mitochondrial adaptability involve the regulations in mitochondrial DNA（mtDNA）content，mitochondrial mass，mitochondrial respiratory capacity，mitochondrial biogenesis，mitochondrial dynamics，and selective elimination of damaged mitochondria（i.e.，mitophagy）.By these mechanisms，mitochondrial activity could be turned up or down and mitochondrial network could be stronger or weaker.Furthermore，mitochondria are centered to switch energy metabolic signals to cell signaling responsible for the whole-cell phenotype，which represents a phenotypic feature with metabolic flexibility or inflexibility.In contrast to the role of mitochondrial abnormality in non-communicable chronic diseases（NCDs）and metabolic disorders，mitochondrial-centered cell signaling may be well adapted to exercise and capable of inducing a phenotype with greater metabolic flexibility.

A great challenge to this is diversity of the human nuclearmitochondrial genotype and the influence of environmental factors.For example，the mitochondrial phenotype is dynamically regulated by diet.28Moreover，humans and other primates have acquired hundreds of active“foreign”genes concerned with metabolism through horizontal gene transfer（HGT）.29HGT is an important driving force to induce mitochondrial intron diversity，promote intron mobility and consequently shape mitochondrial genome architecture.30Mitochondrial DNA （mtDNA）polymorphism modulates the effects of coffee or alcohol consumption on the risk of hypertension，dyslipidemia，glucose intolerance，and hyperuricemia.31，32In addition，endurance performance and trainability in humans were associated with the polymorphism of mtDNA，intron MYL1，angiotensin I-converting enzyme（ACE），and manganese superoxide dismutase（MnSOD）.33-35The ACE polymorphism alters mitochondrial metabolism and muscle energy supply in response to exercise through a novel expression pathway，which contributes to the varying trainability in endurance performance.36For metabolic disease，exercise is a powerful stimulus capable of restoring the metabolic flexibility of fuel selection in genetically-susceptible individuals.37Thus，mitochondrial phenotype is potentially determined by the combination of diet，muscle activity，and genotype.A recent report indicates that standard pharmacological methods are not sufficient to thoroughly predict a patient’s phenotype in response to drug treatment，because the cytochrome P450 （CYP）enzymes responsible for drug clearance have more than 6000 single nucleotide variants distributed across 57 human CYP genes.38Similarly，inter-individual variability in mitochondrial phenotype persists as a major problem for exercise as a medicine for NCDs.We need to re-evaluate the role of exercise in preventing NCDs and key to this will be understanding variability in mitochondrial phenotypes for optimizing therapeutic effects of exercise.

4.Conclusion

The global promotion of PA has not been effective at controlling the prevalence of NCDs.Evolutionarily and mechanistically，energy balance is being challenged by unhealthy diets and physical inactivity，which are known as the contributors to metabolic disorders and NCDs.PA is，for example，of great value in suppressing various metabolic disorders.In our opinion，the underlying mechanisms for exercise are far from consistent and reliable enough to raise PA up to be a standard medicine for NCDs.To further improve the curative and preventive effects of exercise，we have proposed that targeting the mitochondrial phenotype will be central to delivering on tailored exercise intervention（responses to which depend on lifestyle，genetic，and other molecular information about a person）. A major step toward this goal will be to better understand individual exercise“responsomics”that will identify the responses of key molecules in exercise responsive tissues，thus informing us what exercise is the best for a person.

Acknowledgment

This work was supported by grants from the National NaturalScience Foundation ofChina （No.31300977，31171142），Shanghai Pujiang Program（No.15PJC032），and theKey Laboratory Construction Project of Adolescent Health Assessment and Exercise Intervention of Ministry of Education，China（No.40500-541235-14203/004）.

Authors’contributions

Both authors were involved in the development of this review article.SD proposed the outline of the paper and offered the main opinion.ZQ performed the writing of the paper.Both authors have read and approved the final version of the manuscript and agree with the order of presentation of the authors.

Competing interests

Neither of the authors declare competing financial interests.

References

1.Sacco RL，Smith SC，Holmes D，Shurin S.Accelerating progress on non-communicable diseases.Lancet 2013；382:e4-5.

2.McGuire S.Centers for disease control and prevention.state indicator report on physical activity.Atlanta，GA:U.S.Department of Health and Human Services；2014.p.762-3.

3.General Administration of Sport of China.The official bulletin of public physical activity survey in 2014.China Sports Daily.Available at:http:// read.sportspress.cn/zgtyb/page/1/2015-11-17/01/41061447721264251.pdf；2015［accessed 20.01.016］.

4.World Health Organization.Noncommunicable diseases country profiles. Available at:http://apps.who.int/iris/bitstream/10665/128038/1/9789241 507509_eng.pdf？ua=1；2014［accessed 20.01.2016］.

5.World Health Organization.Noncommunicable diseases country profiles. Available at:http://www.who.int/nmh/countries/chn_en.pdf？ua=1；2011 ［accessed 20.01.2016］.

6.Jaffe S.Planning for US Precision Medicine Initiative underway.Lancet 2015；385:2448-9.

7.Lowell BB，Shulman GI.Mitochondrial dysfunction and type 2 diabetes. Science 2005；307:384-7.

8.Heusch G，Libby P，Gersh B，Yellon D.Cardiovascular remodelling in coronary artery disease and heart failure.Lancet 2014；383:1933-43.

9.Tattersall I.Diet as driver and constraint in human evolution.J Hum Evol 2014；77:141-2.

10.Fildes A，Charlton J，Rudisill C，Littlejohns P.Probability of an obese person attaining normal body weight:cohort study using electronic health records.Am J Public Health 2015；105:e54-9.

11.Bauman AE，Reis RS，Sallis JF，Wells JC.Correlates of physical activity: why are some people physically active and others not？Lancet 2012；380:258-71.

12.Nam M，Choi MS，Jung S，Jung Y.Lipidomic profiling of liver tissue from obesity-prone and obesity-resistant mice fed a high fat diet.Sci Rep 2015；5:16984.doi:10.1038/srep16984

13.Xia SF，Duan XM，Hao LY，Li LT.Role of thyroid hormone homeostasis in obesity-prone and obesity-resistant mice fed a high-fat diet.Metabolism 2015；64:566-79.

14.Joo JI，Oh TS，Kim DH，Choi DK.Differential expression of adipose tissue proteins between obesity-susceptible and-resistant rats fed a high-fat diet. Proteomics 2011；11:1429-48.

15.Wang X，Choi JW，Joo JI，Kim DH.Differential expression of liver proteins between obesity-prone and obesity-resistant rats in response to a high-fat diet.Br J Nutr 2011；106:612-26.

16.Bergouignan A，Rudwill F，Simon C，Blanc S.Physical inactivity as the culprit of metabolic inflexibility:evidence from bed-rest studies.J Appl Physiol 2011；111:1201-10.

17.Alibegovic AC，Sonne MP，Hojbjerre L，Bork-Jensen J.Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men.Am J Physiol Endocrinol Metab 2010；299:E752-63.

18.Lieberman DE.Is exercise really medicine？An evolutionary perspective. Curr Sports Med Rep 2015；14:313-9.

19.Hawley JA，Hargreaves M，Joyner MJ，Zierath JR.Integrative biology of exercise.Cell 2014；159:738-49.

20.Raimundo N.Mitochondrial pathology:stress signals from the energy factory.Trends Mol Med 2014；20:282-92.

21.Morris EM，Jackman MR，Meers GM，Johnson GC.Reduced hepatic mitochondrial respiration following acute high-fat diet is prevented by PGC-1α overexpression.Am J Physiol Gastrointest Liver Physiol 2013；305:G868-80.

22.Wagatsuma A，Kotake N，Kawachi T Shiozuka M.Mitochondrial adaptations in skeletal muscle to hindlimb unloading.Mol Cell Biochem 2011；350:1-11.

23.Michan S.Calorie restriction and NAD（+）/sirtuin counteract the hallmarks of aging.Front Biosci（Landmark Ed）2014；19:1300-19.

24.Steiner JL，Murphy EA，McClellan JL，Carmichael MD.Exercise training increases mitochondrial biogenesis in the brain.J Appl Physiol 2011；111:1066-71.

25.Hood DA，Saleem A.Exercise-induced mitochondrial biogenesis in skeletal muscle.Nutr Metab Cardiovasc Dis 2007；17:332-7.

26.Chandel NS.Evolution of mitochondria as signaling organelles.Cell Metab 2015；22:204-6.

27.Kelly SA，Villena FP，Pomp D.The‘omics’of voluntary exercise:systems approaches to a complex phenotype.Trends Endocrinol Metab 2015；26:673-5.

28.Zlotorynski E.Organelle dynamics:regulation of mitochondrial function by diet.Nat Rev Mol Cell Biol 2015；16:515.doi:10.1038/nrm4049

29.Crisp A，Boschetti C，Perry M，Tunnacliffe A.Expression of multiple horizontally acquired genes is a hallmark of both vertebrate and invertebrate genomes.Genome Biol 2015；16:50.doi:10.1186/s13059 -015-0607-3

30.Wu B，Hao W.Horizontal transfer and gene conversion as an important driving force in shaping the landscape of mitochondrial introns.G3 （Bethesda）2014；4:605-12.

31.Kokaze A，Ishikawa M，Matsunaga N，Karita K.Combined effect of longevity-associated mitochondrial DNA 5178 C/A polymorphism and coffee consumption on the risk of hyper-LDL cholesterolemia in middle-aged Japanese men.J Hum Genet 2010；55:577-81.

32.Kawamoto T，Kokaze A，Ishikawa M，Matsunaga N.Joint effect of longevity-associated mitochondrial DNA 5178 C/A polymorphism and alcohol consumption on risk of hyper-LDL cholesterolemia in middle-aged Japanese men.Lipids Health Dis 2011；10:105.doi:10.1186/1476-511X -10-105

33.Kritchevsky SB， Nicklas BJ， Visser M， Simonsick EM. Angiotensin-converting enzyme insertion/deletion genotype，exercise，and physical decline.JAMA 2005；294:691-8.

34.Dionne FT，Turcotte L，Thibault MC，Boulay MR.Mitochondrial DNA sequence polymorphism，VO2max，and response to endurance training.Med Sci Sports Exerc 1993；25:766-74.

35.Ben-Zaken S，Eliakim A，Nemet D，Kassem E.Increased prevalence of MnSOD genetic polymorphism in endurance and power athletes.Free Radic Res 2013；47:1002-8.

36.Vaughan D，Huber-Abel FA，Graber F，Hoppeler H.The angiotensin converting enzyme insertion/deletion polymorphism alters the response of muscle energy supply lines to exercise.Eur J Appl Physiol 2013；113:1719-29.

37.Stephenson EJ，Hawley JA.Mitochondrial function in metabolic health: a genetic and environmental tug of war.Biochim Biophys Acta 2014；1840:1285-94.

38.Lauschke VM，Ingelman-Sundberg M.Precision medicine and rare genetic variants.Trends Pharmacol Sci 2016；37:85-6.

Peer review under responsibility of Shanghai University of Sport. *Corresponding authors.

E-mail addresses:szding@tyxx.ecnu.edu.cn（S.Ding），qzht79@163.com （Z.Qi）

http://dx.doi.org/10.1016/j.jshs.2016.04.002

2095-2546/©2016 Production and hosting by Elsevier B.V.on behalf of Shanghai University of Sport.This is an open access article under the CC BY-NC-ND license（http://creativecommons.org/licenses/by-nc-nd/4.0/）.