Exerc

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Rece ved / Gel ş: 07.09.2020 · Accepted / Kabul: 2.11.2020 · Publ shed / Yayın Tar h : 27.01.2021

Correspondence / Yazışma: Şenay Akın · Hacettepe Ün vers tes , Spor B l mler Fakültes , Egzers z ve Spor F zyoloj s , Ankara, Turkey · senaya@hacettepe.edu.tr

Rev ew Art cle / Derleme

Exerc se, m tochondr al b ogenes s and d suse- nduced atrophy Egzers z, m tokondr yal b yogenez ve kullanılmama atrof s

Şenay Akın¹ , Gökhan Burç n Kubat^1,2 , Haydar A. Dem rel^1,3

1Exerc se and Sport Phys ology Department, Faculty of Sport Sc ences, Hacettepe Un vers ty, Ankara, Turkey 2Department of Pathology, Gulhane Tra n ng and Research Hosp tal, Ankara, Turkey 3Department of Sports Med c ne, Faculty of Med c ne, Hacettepe Un vers ty, Ankara, Turkey

ABSTRACT

In addition to the physiological and cellular effects of exercise, many studies demonstrated that exercise could prevent skeletal muscle atrophy due to disuse. Mitochondria, which are powerhouses in cells, are at the top of the molecular mechanisms that control muscle function. Mitochondria play an essential role in regulating protein synthesis and degradation through various signaling pathways such as ubiquitin-proteolysis, mitochondrial biogene‐

sis, fusion, and ﬁssion dynamics autophagy, and apoptosis. Regular exercise protects the skeletal muscle against different stresses by improving cel‐

lular oxidative capacity. Eventually, exercise controls the expression of proteins that have been shown to protect muscle from atrophy caused by disu‐

se and activates many cellular signaling pathways. In this review, the role of mitochondria in muscle cells, the effect of disuse atrophy on mitochond‐

ria, and the effect of exercise on peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) that plays a crucial role in mitochondrial bi‐

ogenesis are discussed.

Keywords: muscle atrophy, fusion and ﬁssion dynamics, Ca²⁺ homeostasis, mitochondrial disease ÖZ

Egzersizin ﬁzyolojik ve hücresel etkilerine ek olarak, birçok çalışma egzersizin ‘kullanılmama’ nedeniyle oluşan iskelet kası atroﬁsini önleyebileceğini göstermiştir. Hücredeki enerji üretim merkezi olan mitokondri, kas fonksiyonunu kontrol eden moleküler mekanizmaların başında gelir. Mitokondri, ubi‐

kitin-proteoliz, mitokondriyal biyogenez, füzyon ve ﬁsyon dinamikleri, otofaji ve apoptoz gibi çeşitli sinyal yolakları aracılığıyla protein sentezini ve degra‐

dasyonun arasındaki dengenin düzenlenmesinde önemli bir rol oynar. Düzenli egzersiz, hücrede oksidatif kapasiteyi artırarak iskelet kasını farklı stresle‐

re karşı korur. Sonuçta egzersiz, iskelet kasını ‘kullanılmama’ nedeniyle oluşan atroﬁden koruduğu bilinen proteinlerin ifadesini kontrol eder ve birçok hücresel sinyal yolunu etkinleştirir. Bu derlemede, mitokondrinin kas hücrelerindeki rolü, kullanılmama atroﬁsinin mitokondri üzerindeki etkisi ve egzersi‐

zin PGC-α1 üzerindeki etkisi ve mitokondriyal biyogenezde oynadığı önemli rol tartışılmıştır.

Anahtar Sözcükler: kas atroﬁsi, füzyon ve ﬁsyon dinamikleri, Ca²⁺ homeostazisi, mitokondriyal hastalıklar

INTRODUCTION

Skeletal muscles const tut ng 40-45% of human body we- ght, are respons ble for the force product on, body move- ment and breath ng as well as glycem c control, regulat on of metabol c genes and metabol c homeostas s. In add t on to sarcopen a and cachex a, var ous cond t ons wh ch are known as muscle d suse, where mechan cal load or neural act vat on s lost or reduced such as denervat on, l mb m- mob l zat on, long term bed rest, sedentary l festyle and phys cal nact v ty result n skeletal muscle atrophy (1). The decrease n muscle contract le prote ns w ll cause a decrease n funct onal capac t es such as muscle strength and endurance and qual ty of l fe, as well as metabol c problems such as nsul n res stance and type 2 d abetes, ncrease n morb d ty and mortal ty and prolong recovery a er d seases. As a result, skeletal muscle atrophy br ngs a ser o- us econom c burden on the health care system.

D suse atrophy results n reduct on of the cross-sect onal area of the nd v dual muscle f bers. On the cellular level, ncrease n prote n breakdown (1), m tochondr al dysfunct - on (2, 3), deter orat on n calc um homeostas s (4), and ncrease n react ve oxygen spec es occur (5, 6).

In skeletal muscle, m tochondr a are respons ble for ATP product on through ox dat ve pathways and are part cularly s gn f cant for metabol c processes and contract on funct - ons (7). However, n advanced cond t ons, nclud ng exerc - se or mmob l zat on, m tochondr a play a cr t cal role n regulat ng redox homeostas s and apoptos s, controll ng the balance between react ve oxygen spec es (ROS) produc- t on and ant ox dant defense system (8, 9).

Although there s a great deal of ev dence for the preservat - on of m tochondr al funct ons w th certa n chem cal agents

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(10, 11), exerc se s known to be the most e ect ve treatment n mprov ng muscle mass and strength and preserv ng m - tochondr al funct ons. Th s rev ew focused on a br ef d s- cuss on on m tochondr al dysfunct ons caused by mmob - l zat on and the mportance of regular exerc se n m tochondr al protect on.

The role of mitochondria in disuse atrophy Energy product on

Adenos ne tr phosphate (ATP) s produced n m tochondr a, and the cell uses ATP as the only energy form. The pr mary role of m tochondr a s to convert products espec ally from carbohydrate, and fat metabol sm to carbon d ox de and water through the electron transport cha n's key enzymes local zed n the nner membrane. Dur ng these react ons, electrons pass through NADH dehydrogenase (Complex I), succ nate dehydrogenase (Complex II), cytochrome bc1 (Complex III), and cytochrome c ox dase (Complex IV) complexes wh le protons (H⁺) are pumped from the matr x nto the ntermembrane space (F g. 1). Thus, a proton grad - ent s formed, and th s grad ent s v tal n perform ng ATP synthes s by the ATP synthase enzyme (Complex V). Th s process, called ox dat ve phosphorylat on, nvolves the product on of ATP by ox dat on of substrates n the m tochond- r a, and the regular funct on ng of th s process s extremely cr t cal for var ous t ssues and organs.

Figure 1. M tochondr al Electron Transport Cha n. The electron transport cha n s a sequence of electron transporters mplanted n the nner m tochondr al membrane that transports electrons from NADH and FADH₂ to molecular oxygen.

ROS generat on

Dur ng energy product on by ox dat ve phosphorylat on, the products com ng from glycolys s and Krebs cycle pas- s ng through the electron transfer cha n (ETC), some oxygen (0.2% - 2%) taken nto the cells even under normal con- d t ons are transformed nto ROS (12). Th s s because the electrons com ng to the ETC accumulate as protons pass th-

rough complex I and III and comb ne w th oxygen. Elect- rons comb ned d rectly w th oxygen form the superox de an on and w th further reduct on, the hydroxyl rad cal (OH^.), a powerful ox d zer. Dysfunct on of these m tochond- r al complexes may also play an essent al role n the patho- genes s of some chron c d seases, as a deter orat on n m - tochondr al funct on o en accompan es the occurrence of metabol c d sorders.

Ca²⁺ homeostas s

In add t on to produc ng energy n the cell, m tochondr a also perform a cruc al funct on n ma nta n ng ntracellular calc um (Ca²⁺) balance. Prec se regulat on of Ca²⁺ uptake and release to the cytoplasm s necessary to ma nta n Ca²⁺homeostas s regard ng cellular funct ons. M tochond- r a respond to calc um concentrat on changes v a m tochondr al calc um bu er ng capac ty and by nteract ng w th other channels or organelles to keep the ntracellular Ca²⁺concentrat on at a certa n level (13). Indeed, a network of Ca²⁺ transport and bu er ng systems regulate ntracellular Ca²⁺ concentrat on. The endoplasm c ret culum (ER) ac- t ng as Ca²⁺storage w th n the cell and m tochondr a are n contact to control ntracellular Ca²⁺homeostas s. Th s contact s except onally cr t cal n regulat ng aerob c metabo- l sm and cell surv val (14, 15). Exposure to h gh concentrat - ons of Ca²⁺ for a long t me negat vely a ects v tal act v t es (16). Moreover, a d srupt on n Ca²⁺transfer between the sarcoplasm c ret culum and m tochondr a causes an ncrease n Ca²⁺concentrat on and th s ncrease s a s gnal that act vates apoptos s-related mechan sms n the cell (16, 17).

The mitochondrial adaptation to disuse atrophy M tochondr a are programmed to adapt to the var ous con- d t ons s nce they have to prov de the requ red energy for cont nu ng cellular processes n skeletal muscle. These adaptat ons are regulated by fus on and f ss on events (F g.

2). Excess ve ROS product on s known to be closely assoc - ated w th skeletal muscle atrophy n m ce (18). However, the exact mechan sm s st ll unclear. Fus on and f ss on are not only nvolved n the structural regulat on of m tochond- r a but are also remarkably mportant n transm tt ng ntracellular ROS product on-related redox s gnals and regula- t ng apoptos s pathways (19, 20). Two of the best character - zed m tochondr al fus on factors are m tofus n 1 and 2 (Mfn1/2), respons ble for the attachment and fus on of outer m tochondr al membranes (21). Opt c atrophy prote n 1 (OPA1) controls the m tochondr al nner membrane fus on (22). Concurrently, two essent al prote ns that promote m - tochondr al f ss on nclude dynam n-related prote n-1 (Drp1) and F ss on 1 (F s1).

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Figure 2. M tochondr al adaptat on dur ng d suse atrophy. The fus on progress on requ res m tochondr al outer membrane fus on v a Mfn1/2 and m tochondr al

nner membrane fus on v a Opa1.

There s ev dence that the ncrease n m tochondr al f ss on s assoc ated w th ncreased apoptos s n some cell types and ncreased atrophy n skeletal muscle f bers (19, 23, 24).

For nstance, t has been shown that Drp1 act v ty nh b t - on may delay caspase act vat on and apoptot c cell death n cells exposed to apoptot c st mul . Moreover, the nh b t on of F s1 may also protect aga nst apoptos s, wh le the overexpress on of F s1 promotes apoptot c cell death (19). S m - larly, m ce lack ng Mfn1/2 n skeletal muscle exh b t both m tochondr al dysfunct on and profound muscle atrophy (25). It has also been shown rregular ty of the m tochondr - al nner membrane, the release of cytochrome c, and ncreased apoptos s n cells lack ng Opa1 (26).

The plast c ty of skeletal muscle largely depends on m tochondr a's ab l ty to change the r shape and s ze n response to both ntracellular and extracellular s gnals (27). Many stud es suggested that d suse negat vely a ects m tochond- r al homeostas s, and t may be the pr mary cause of defects n muscle structure and funct on (28). Indeed, exper mental atrophy models have shown a s gn f cant reduct on n m - tochondr a dens ty. For example, Kang et al. showed that the m tochondr al dens ty n m ce t b al s anter or muscle decreased a er the 14-day h ndl mb mmob l zat on (29).

M tochondr al b ogenes s s organ zed pr nc pally by pero- x some-prol ferator act vated receptor γ (PPARγ) andperox - some prol ferator-act vated receptor-gamma coact vator-1α

(PGC-1α) n wh ch st mulates the express on of nuclear-en- coded m tochondr al prote ns Nrf-1 (Nuclear resp ratory factor 1) and Nrf-2(Nuclear resp ratory factor 2), and Tfam (Transcr pt on factor A, m tochondr al), the key controller of m tochondr al DNA (mtDNA) b osynthes s (30). Kang et al. emphas zed that PGC1α express on, wh ch plays an essent al role n m tochondr al b ogenes s, s suppressed du- r ng mmob l zat on. Moreover, a er f ve days of remob l za- t on follow ng 14 days of h ndl mb mmob l zat on, PGC1α express on decreased n TA (t b al s anter or) muscle and then reached control levels on the 10th day of remob l zat - on. The same study reported that PGC1α overexpress on also mproved the ox dant-ant ox dant balance (31). S m - larly, 14-day denervat on causes a decrease n muscle cross- sect onal area. Nrf2 levels are also s gn f cantly reduced (32), accompan ed by a decrease n Tfam (29).

M tochondr al caspase-3 dependent apoptos s s another cr t cal s gnal ng pathway n d suse- nduced muscle atrophy (33). Impa rment of calc um homeostas s dur ng d - suse causes an ncrease n ntracellular calc um concentra- t on and act vates caspase-3, wh ch s nvolved n prote n degradat on n the cell (34). Bes des, ncreas ng Ca²⁺ levels tr ggers the act vat on of the pro-apoptot c prote n Bax to the m tochondr a's outer membrane by creat ng Bax/Bax- homo-ol gomer zat on. Bcl2, an ant -apoptot c Bcl-2 fam ly prote n that nh b ts Bax, can prevent the format on of Bax/Bax-homo-ol gomer zat on. The reduct on n the Bax/Bcl-2 rat o leads to pro-apoptot c release from m tochondr a that act vate caspase-9 and caspase-3 (35). Hu et al.

reported an ncrease n Bax/Bcl-2 and cytochrome C release from m tochondr a n the gastrocnem us a er 14 days of HLU (36). Therefore, both ROS overproduct on and Ca²⁺

overload play an mportant role n d srupt ng prote n synthes s follow ng mmob l zat on.

Many stud es have been conducted n recent years, empha- s z ng the mportance of m tochondr al ntegr ty n d suse- nduced muscle atrophy n skeletal muscle cells. Among these stud es, the mportance of PGC-1α was noted not only n ma nta n ng a healthy muscle mass, but also n terms of suscept b l ty to metabol c d seases (37). Indeed, the mul- t ple roles and apoptot c cascades of PGC-1α n the cell to control m tochondr al b ogenes s and fus on-f ss on dyna- m cs have ga ned mportance for muscle phys ology research. Th s shows that expla n ng the cellular mechan sms of muscle atrophy can prov de nformat on for develop ng relevant treatment strateg es for pat ents su er ng from muscle wast ng.

Exercise and mitochondrial biogenesis

Exerc se pos t vely a ects mult ple organ systems, nclu- d ng the musculoskeletal system. Many stud es demonstra‑

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te that a sedentary l festyle s gn f cantly ncreases the rela- t ve r sk of var ous chron c d seases such as coronary artery d sease, nsul n res stance, type 2 d abetes, osteoporos s, and some cancers (38-40). On the other hand, regular exer- c se s s gn f cantly assoc ated w th ncreased l fe expec- tancy and qual ty (41) and may also be benef c al to mode- rate or slow the progress on of many metabol c d seases such as obes ty, metabol c syndrome, type 2 d abetes. Inde- ed, regular exerc se s known to mprove metabol c gene regulat on and glycem c control and ncrease whole-body oxygen uptake capac ty (42).

The most prom nent response of organ sms to external stress factors that ncrease the need for aerob cally produced energy s m tochondr al resp rat on adaptat ons. These adaptat ons have nvolved some mod f cat ons n the m tochondr a, fac l tat ng the d us on of O₂ and substrates used for ATP synthes s to prov de the energy requ red n stress cond t ons. Increased energy requ rement dur ng exerc se s essent al n m tochondr al b ogenes s. The energy requ rements of the cell are fulf lled by regulat ng the s ze and content of m tochondr a n response to exerc se. Indeed, even an acute exerc se can tr gger m tochondr al regulat on (43).

The role of PGC-1 appears to be prom nent n most stud es expla n ng the role of exerc se n m tochondr al b ogenes s.

PGC-1α has been shown to nteract d rectly and act vate mult ple nuclear receptors to ncrease ox dat ve metabol sm and m tochondr al b ogenes s n most cell types (F gure-3).

Overexpress on of PGC-1α n muscle t ssue of transgen c m ce act vates m tochondr al b ogenes s, lead ng to an ncrease n type I and ox dat ve type IIa f bers and consequ- ently, an ncrease n res stance to muscle fat gue (44). In contrast, the absence of PGC-1α n muscle leads to a s gn f - cant reduct on of m tochondr al resp rat on, gene express - on encod ng enzymes n the electron transfer cha n and reduced exerc se performance (28).

Exerc se st mulates m tochondr al b ogenes s n skeletal muscle follow ng acute exerc se by var ous cellular s gnals:

a) ncreased ntracellular Ca2+ concentrat on and b) energy balance d srupt on due to muscle contract on. These s g- nals caused by exerc se nduce the express on of PGC-1α, nuclear resp ratory factors 2 (NRF-2) and m tochondr al transcr pt on factor A (Tfam) n the nucleus (45). Dur ng muscle contract on, ncreased Ca²⁺ concentrat on act vates the PGC-1α transcr pt on through calc um-dependent prote- n phosphatase, calc neur n and calmodul n-dependent k - nase. It has been shown that PGC-1α s a part cular element for type I f bers that use energy n the skeletal muscle aero- b cally (44). On the other hand, m ce w th skeletal muscle- spec f c PGC-1-KO (PGC-1-MKO) have d splayed a decreased

max mum exerc se capac ty, muscle funct on damage and decreased ox dat ve metabol sm capac ty (46).

Figure 3. Exercise eﬀects on mitochondrial biogenesis : Exercise triggers mitochondrial biogenesis in skeletal muscle by the activation of various signaling pathways. PGC-1α translocates to the nucleus to stimulate transcription factors and nuclear receptors. AMPK: 5′ AMP-act vated prote n k nase; NRF1: nuclear resp ratory factor-1; PGC-1α:

perox some prol ferator-act vated receptor gamma coact vator 1-alpha; Tfam: Transcr pt on factor A, m tochondr al.

The deter orat on n the ATP/ADP rat o dur ng exerc se act - vates AMP-act vated prote n k nase (AMPK) (47). AMPK phosphorylat on results n the phosphorylat on of PGC-1α (48, 49). It has been reported that the ncrease n AMPK phosphorylat on n skeletal muscle s an mportant factor to act vate the m tochondr al funct on of PGC-1α (50). PGC- 1α s mostly found n the cytosol n an nact ve form n the rest ng state, but when exposed to stress such as endurance exerc se, PGC-1α s phosphorylated and translocated from the cytosol to the nucleus, and the nuclear prote n level ncreases. It has also been reported that PGC-1α pass ng nto the nucleus also a ects the express on of Tfam (51).

Protective role of exercise on mitochondria during disuse

D suse atrophy causes a decrease n prote n synthes s and an ncrease n degradat on, caus ng skeletal muscle mass loss. It also causes m tochondr al dysfunct on, creat ng a decrease n phys cal performance and reduc ng l fe qual ty.

An ncrease n react ve oxygen spec es and m tochondr al dysfunct on n d suse atrophy act vate prote n degradat ons and cell apoptos s s gnal ng pathways (52, 53).

It s well known that regular exerc se has pos t ve phys olo- g cal e ects on the card opulmonary and neuroendocr ne systems (54). Bes des, exerc se causes phenotyp c changes, nclud ng cross-sect onal muscle area, cap llary dens ty, f‑

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ber type trans t on (55) and m tochondr al b ogenes s, result ng n ncreased performance (56).

The fact that PGC1-α act vat on ncreases w th exerc se and decreases n d suse cond t ons (28) suggest that PGC1-α has a v tal role n cellular protect on. Therefore, s nce h gh- n- tens ty endurance exerc ses w ll ncrease PGC1-α act vat on (57), regular endurance exerc ses w ll enable PGC1-α to be act ve (58, 59). Bes des, human and an mal stud es have shown that an ncrease n ant ox dant defense w th exerc - se preserves m tochondr al b ogenes s n a cond t on of subsequent atrophy (60, 61). t has also been determ ned that exerc se causes an ncrease n m tochondr a fus on by

ncreas ng the express on of Mfn1 / 2 prote ns (43, 62).

Mitochondrial disease and exercise

M tochondr al d seases nclude rare d seases that develop due to ox dat ve phosphorylat on d sorders n m tochondr a caused by mutat ons n m tochondr al DNA (mtDNA) (63).

The organs w th h gher metabol c requ rements, espec ally the skeletal muscle are negat vely a ected by th s cond t - on. M tochondr al myopathy, nadequate exerc se capac ty and low aerob c performance levels n skeletal muscle character ze m tochondr al d sease (64). Although t s one of the most common neuromuscular d sorders, t shows a va- r able est mated prevalence (65). For nstance, Jeppesen et al. reported that 12 weeks of aerob c exerc se s gn f cantly mproved max mum ox dat ve capac ty n 20 pat ents w th four d erent mtDNA mutat on types and var ous mutant loads. Th s mprovement d d not s gn f cantly a ect act v t - es of da ly l v ng n asymptomat c carr ers of mtDNA muta- t ons; however, VO2max mprovement s s gn f cant n pat - ents w th severe ox dat ve defects (66). S m larly, Ta vassalo et al. reported n a study nvolv ng ten pat ents w th var ous heteroplasm c mtDNA defects that a 14-week cycl ng exerc - se mproved the pat ents' qual ty of l fe by ncreas ng exer- c se capac ty and max mum O₂ ut l zat on (67). Th s study has shown that 14 weeks of tra n ng ncreased ox dat ve capac ty by 20-30% and system c arter ovenous O2 d erence by 20%. They also reported that n pat ents w th Complex I and Complex IV defects, m tochondr al volume ncreased by 50% n b opsy samples taken from the vastus lateral s muscle and accompan ed by ncreases n defect ve resp ratory cha n enzymes (67). These results are emphas z ng that exerc se may be a valuable method mprov ng pat ents' qual ty of l fe by ncreas ng exerc se capac ty, max mum O2 ut l zat on, and endurance capac ty for pat ents w th m tochondr al d sease (67, 68). Res stance exerc ses also tr gger m tochondr al b ogenes s n skeletal muscle cells (69) and cause an ncrease n muscle mass and strength (70).

Murphy et al. showed that a 12-week res stance exerc se on e ght pat ents w th large-scale delet ons n mtDNA mpro-

ved strength and a reduced m tochondr al DNA heteropla- s a w thout any s de e ects (71).

CONCLUSION

Compl cat ons n m tochondr al b ogenes s occurr ng n the muscle cell contr bute s gn f cantly many health problems start ng from the cellular level to ncreas ng suscept b l ty to some chron c d seases. M tochondr a are suscept ble to s gnals that occur n response to muscle contract on. There- fore, exerc se plays an essent al role n regulat ng m tochondr al b ogenes s and ma nta n ng ts funct on. PGC-1 s a gene express on coact vator that controls m tochondr al b ogenes s n muscle. Improvement of our understand ng of exerc se that regulates m tochondr al b ogenes s and muscle funct on s cr t cal for ma nta n ng whole-body metabol c health.

Conﬂict of Interest / Çıkar Çatışması

The authors declared no con cts of nterest w th respect to authorsh p and/or publ cat on of the art cle.

Financial Disclosure / Finansal Destek

The authors rece ved no f nanc al support for the research and/or publ - cat on of th s art cle.

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