Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-23a has minimal effect on endurance exercise-induced adaptation of mouse skeletal muscle

  • Muscle physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Skeletal muscles contain several subtypes of myofibers that differ in contractile and metabolic properties. Transcriptional control of fiber-type specification and adaptation has been intensively investigated over the past several decades. Recently, microRNA (miRNA)-mediated posttranscriptional gene regulation has attracted increasing attention. MiR-23a targets key molecules regulating contractile and metabolic properties of skeletal muscle, such as myosin heavy-chains and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α). In the present study, we analyzed the skeletal muscle phenotype of miR-23a transgenic (miR-23a Tg) mice to explore whether forced expression of miR-23a affects markers of mitochondrial content, muscle fiber composition, and muscle adaptations induced by 4 weeks of voluntary wheel running. When compared with wild-type mice, protein markers of mitochondrial content, including PGC-1α, and cytochrome c oxidase complex IV (COX IV), were significantly decreased in the slow soleus muscle, but not the fast plantaris muscle of miR-23a Tg mice. There was a decrease in type IId/x fibers only in the soleus muscle of the Tg mice. Following 4 weeks of voluntary wheel running, there was no difference in the endurance exercise capacity as well as in several muscle adaptive responses including an increase in muscle mass, capillary density, or the protein content of myosin heavy-chain IIa, PGC-1α, COX IV, and cytochrome c. These results show that miR-23a targets PGC-1α and regulates basal metabolic properties of slow but not fast twitch muscles. Elevated levels of miR-23a did not impact on whole body endurance capacity or exercise-induced muscle adaptations in the fast plantaris muscle.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ALS:

Amyotrophic lateral sclerosis

COX IV:

Cytochrome c oxidase subunit IV

miRNA:

MicroRNA

MyHC:

Myosin heavy-chain

NFAT:

Nuclear factor of activated T cells

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha

Tg:

Transgenic

UTR:

Untranslated region

WT:

Wild-type

References

  1. Akimoto T, Okuhira K, Aizawa K, Wada S, Honda H, Fukubayashi T, Ushida T (2013) Skeletal muscle adaptation in response to mechanical stress in p130Cas−/−mice. Am J Physiol Cell Physiol 304:C541–C547

    Article  CAS  PubMed  Google Scholar 

  2. Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z (2005) Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 280:19587–19593

    Article  CAS  PubMed  Google Scholar 

  3. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO (2002) Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J 16:1879–1886

    Article  CAS  PubMed  Google Scholar 

  4. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  5. Brown M, Ross TP, Holloszy JO (1992) Effects of ageing and exercise on soleus and extensor digitorum longus muscles of female rats. Mech Ageing Dev 63:69–77

    Article  CAS  PubMed  Google Scholar 

  6. Carrer M, Liu N, Grueter CE, Williams AH, Frisard MI, Hulver MW, Bassel-Duby R, Olson EN (2012) Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378. Proc Natl Acad Sci U S A 109:15330–15335

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38:228–233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, Shelton JM, Wu H, Zhu W, Bassel-Duby R, Williams RS (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12:2499–2509

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Chinsomboon J, Ruas J, Gupta RK, Thom R, Shoag J, Rowe GC, Sawada N, Raghuram S, Arany Z (2009) The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci U S A 106:21401–21406

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Finck BN, Kelly DP (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest 116:615–622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Geng T, Li P, Okutsu M, Yin X, Kwek J, Zhang M, Yan Z (2010) PGC-1alpha plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscle. Am J Physiol Cell Physiol 298:C572–C579

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Goto M, Terada S, Kato M, Katoh M, Yokozeki T, Tabata I, Shimokawa T (2000) cDNA Cloning and mRNA analysis of PGC-1 in epitrochlearis muscle in swimming-exercised rats. Biochem Biophys Res Commun 274:350–354

    Article  CAS  PubMed  Google Scholar 

  13. Grueter CE, van Rooij E, Johnson BA, DeLeon SM, Sutherland LB, Qi X, Gautron L, Elmquist JK, Bassel-Duby R, Olson EN (2012) A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Cell 149:671–683

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Hamilton AJ, Baulcombe DC (1999) A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286:950–952

    Article  CAS  PubMed  Google Scholar 

  15. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 282:30014–30021

    Article  CAS  PubMed  Google Scholar 

  16. Holloszy JO (1967) Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. J Biol Chem 242:2278–2282

    CAS  PubMed  Google Scholar 

  17. Ikeda S, Kawamoto H, Kasaoka K, Hitomi Y, Kizaki T, Sankai Y, Ohno H, Haga S, Takemasa T (2006) Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouseskeletal muscle. Acta Physiol (Oxf) 188:217–223

    Article  CAS  PubMed  Google Scholar 

  18. Katzmarzyk PT, Janssen I (2004) The economic costs associated with physical inactivity and obesity in Canada: an update. Can J Appl Physiol 29:90–115

    Article  PubMed  Google Scholar 

  19. Kim HK, Lee YS, Sivaprasad U, Malhotra A, Dutta A (2006) Muscle-specific microRNA miR-206 promotes muscle differentiation. J Cell Biol 174:677–687

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Kinugawa S, Wang Z, Kaminski PM, Wolin MS, Edwards JG, Kaley G, Hintze TH (2005) Limited exercise capacity in heterozygous manganese superoxide dismutase gene-knockout mice: roles of superoxide anion and nitric oxide. Circulation 111:1480–1486

    Article  CAS  PubMed  Google Scholar 

  21. Li P, Akimoto T, Zhang M, Williams RS, Yan Z (2006) Resident stem cells are not required for exercise-induced fiber-type switching and angiogenesis but are necessary for activity-dependent muscle growth. Am J Physiol Cell Physiol 290:C1461–C1468

    Article  CAS  PubMed  Google Scholar 

  22. Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773

    Article  CAS  PubMed  Google Scholar 

  23. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801

    Article  CAS  PubMed  Google Scholar 

  24. McCarthy JJ, Esser KA, Peterson CA, Dupont-Versteegden EE (2009) Evidence of MyomiR network regulation of beta-myosin heavy chain gene expression during skeletal muscle atrophy. Physiol Genomics 39:219–226

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nachlas MM, Tsou KC, de Souza E, Cheng CS, Seligman AM (1957) Cytochemical demonstration of succinic dehydrogenase by the use of a new p-nitrophenyl substituted ditetrazole. J Histochem Cytochem 5:420–436

    Article  CAS  PubMed  Google Scholar 

  26. Naumann K, Pette D (1994) Effects of chronic stimulation with different impulse patterns on the expression of myosin isoforms in rat myotube cultures. Differentiation 55:203–211

    Article  CAS  PubMed  Google Scholar 

  27. Nielsen S, Scheele C, Yfanti C, Akerstrom T, Nielsen AR, Pedersen BK, Laye MJ (2010) Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle. J Physiol 588:4029–4037

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Okabe M, Ikawa M, Kominami K, Nakanishi T, Nishimune Y (1997) 'Green mice' as a source of ubiquitous green cells. FEBS Lett 407:313–319

    Article  CAS  PubMed  Google Scholar 

  29. Pogozelski AR, Geng T, Li P, Yin X, Lira VA, Zhang M, Chi JT, Yan Z (2009) P38Gamma mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice. PLoS One 4:e7934

    Article  PubMed Central  PubMed  Google Scholar 

  30. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839

    Article  CAS  PubMed  Google Scholar 

  31. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906

    Article  CAS  PubMed  Google Scholar 

  32. Riedy M, Moore RL, Gollnick PD (1985) Adaptive response of hypertrophied skeletal muscle to endurance training. J Appl Physiol 59:127–131

    CAS  PubMed  Google Scholar 

  33. Rodnick KJ, Henriksen EJ, James DE, Holloszy JO (1992) Exercise training, glucose transporters, and glucose transport in rat skeletal muscles. Am J Physiol 262:C9–C14

    CAS  PubMed  Google Scholar 

  34. Rowe GC, El-Khoury R, Patten IS, Rustin P, Arany Z (2012) PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle. PLoS One 7:e41817

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, Greene NP, Wu J, Estall JL, Irving BA, Lanza IR, Rasbach KA, Okutsu M, Nair KS, Yan Z, Leinwand LA, Spiegelman BM (2012) A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151:1319–1331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, Dériaz O (2003) Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 52:2874–2881

    Article  CAS  PubMed  Google Scholar 

  37. Russell AP, Wada S, Vergani L, Hock MB, Lamon S, Léger B, Ushida T, Cartoni R, Wadley GD, Hespel P, Kralli A, Soraru G, Angelini C, Akimoto T (2012) Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis. Neurobiol Dis 49C:107–117

    Google Scholar 

  38. Russell AP, Lamon S, Boon H, Wada S, Guller I, Brown EL, Chibalin AV, Zierath J, Snow RJ, Stepto NK, Wadley GD, Akimoto T. (2013) Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short term endurance training. J Physiol. 2013; (in press)

  39. Safdar A, Abadi A, Akhtar M, Hettinga BP, Tarnopolsky MA (2009) miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6 J male mice. PLoS One 4:e5610

    Article  PubMed Central  PubMed  Google Scholar 

  40. Schiaffino S, Gorza L, Sartore S, Saggin L, Ausoni S, Vianello M, Gundersen K, Lømo T (1989) Three myosin heavy chain isoforms in type 2 skeletal muscle fibres. J Muscle Res Cell Motil 10:197–205

    Article  CAS  PubMed  Google Scholar 

  41. Schiaffino S, Reggiani C (2011) Fiber types in mammalian skeletal muscles. Physiol Rev 91:1447–1531

    Article  CAS  PubMed  Google Scholar 

  42. Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T, Tabata I (2002) Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. Biochem Biophys Res Commun 296:350–354

    Article  CAS  PubMed  Google Scholar 

  43. Terada S, Tabata I (2004) Effects of acute bouts of running and swimming exercise on PGC-1alpha protein expression in rat epitrochlearis and soleus muscle. Am J Physiol Endocrinol Metab 286:E208–E216

    Article  CAS  PubMed  Google Scholar 

  44. Thyfault JP, Cree MG, Zheng D, Zwetsloot JJ, Tapscott EB, Koves TR, Ilkayeva O, Wolfe RR, Muoio DM, Dohm GL (2007) Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism. Am J Physiol Cell Physiol 292:C729–C739

    Article  CAS  PubMed  Google Scholar 

  45. van Rooij E, Quiat D, Johnson BA, Sutherland LB, Qi X, Richardson JA, Kelm RJ Jr, Olson EN (2009) A family of microRNAs encoded by myosin genes governs myosin expression and muscle performance. Dev Cell 17:662–673

    Article  PubMed Central  PubMed  Google Scholar 

  46. Wada S, Kato Y, Okutsu M, Miyaki S, Suzuki K, Yan Z, Schiaffino S, Asahara H, Ushida T, Akimoto T (2011) Translational suppression of atrophic regulators by microRNA-23a integrates resistance to skeletal muscle atrophy. J Biol Chem 286:38456–38465

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Wang L, Chen X, Zheng Y, Li F, Lu Z, Chen C, Liu J, Wang Y, Peng Y, Shen Z, Gao J, Zhu M, Chen H (2012) MiR-23a inhibits myogenic differentiation through down regulation of fast myosin heavy chain isoforms. Exp Cell Res 318:2324–2334

    Article  CAS  PubMed  Google Scholar 

  48. Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han DH, Chen MM, Hancock CR, Lehman JJ, Huss JM, McClain DA, Holloszy JO, Kelly DP (2007) A role for the transcriptional coactivator PGC-1alpha in muscle refueling. J Biol Chem 282:36642–36651

    Article  CAS  PubMed  Google Scholar 

  49. Wu H, Rothermel B, Kanatous S, Rosenberg P, Naya FJ, Shelton JM, Hutcheson KA, DiMaio JM, Olson EN, Bassel-Duby R, Williams RS (2001) Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. EMBO J 20:6414–6423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317

    Article  CAS  PubMed  Google Scholar 

  51. Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Hiroshi Sagara (The University of Tokyo) and Akisa Tobimatsu for excellent technical support. The authors also thank Dr. Stefano Schiaffino (Venetian Institute for Molecular Medicine) for comments on EM images. This study was supported in part by Grants-in Aid for Young Investigators (A; 21680049 to T. A.) and for Scientific Research (B; 25282198 to T. A.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Takeda Science Foundation. S. W., K. A. and J. H. P. were supported by Japan Society of the Promotion of Science (JSPS).

Author information

Authors and Affiliations

  1. Division of Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-0033, Japan

    Shogo Wada, Katsuji Aizawa, Jong-Hoon Park, Takashi Ushida & Takayuki Akimoto

  2. Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, 305-8562, Japan

    Yoshio Kato

  3. Cooperative Major in Advanced Health Science, Tokyo University of Agriculture and Technology/Waseda University, Mikajima 3-8-1, Tokorozawa, Saitama, 359-1192, Japan

    Shuji Sawada

  4. Department of Physical Education, Konkuk University, Seoul, 143-701, Korea

    Jong-Hoon Park

  5. Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125, Australia

    Aaron P. Russell

Authors
  1. Shogo Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshio Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuji Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Katsuji Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jong-Hoon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aaron P. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takashi Ushida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takayuki Akimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takayuki Akimoto.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wada, S., Kato, Y., Sawada, S. et al. MicroRNA-23a has minimal effect on endurance exercise-induced adaptation of mouse skeletal muscle. Pflugers Arch - Eur J Physiol 467, 389–398 (2015). https://doi.org/10.1007/s00424-014-1517-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1517-z

Keywords

Search

Navigation