Yan Laboratory
Exercise Physiology

Center for Skeletal Muscle Research
Robert M. Berne Cardiovascular Research Center
University of Virginia School of Medicine
409 Lane Road, MR4 - 6041A
Charlottesville, VA 22908
Phone: 434-982-4477
Fax: 434-982-3139

Research Topics in Yan Lab

Molecular mechanism of exercise training-induced skeletal muscle adaptation
Since antiquity regular exercise has been known to have profound benefits, including enhanced performance and healthy longevity. The benefits of exercise are mainly mediated by skeletal muscle adaptation. In particular, mitochondrial remodeling plays critical roles. Research in this laboratory has focused on mitochondrial biogenesis and mitophagy in skeletal muscle. Our earlier findings revealed that mitogen-activated protein kinase (MAPK) p38γ isoform, but not p38α or p38b isoform, is critical for exercise training-induced mitochondrial biogenesis through peroxisome proliferator activated receptor γ co-activator-1α (Pgc-1α). We have recently developed a novel mitochondrial reporter gene, MitoTimer, and inducible MitoTimer reporter mice for assessing mitochondrial content, size, oxidative stress and mitophagy in vivo. Our more recent work revealed that exercise training promotes mitophagy. We now study the regulation and functional importance of exercise training-induced mitophagy in metabolic and contractile adaptations.
A novel mitochondrial reporter gene for mitochondrial quality in adult mouse skeletal muscle (Laker et al. J Biol Chem, 2014)
Muscle-specific p38gamma knockout (MKO) mice, but not MKO of p38αlpha or p38beta, have attenuated induction of cytochrome oxidase IV (COX IV) and cytochrome c (Cyt c) in plantaris muscles following 4 weeks of voluntary running (Pogozelski et al. PLoS One, 2009) Mitochondrial remodeling in response to exercise in skeletal muscle (Drake et al. FASEB J, 2015)
Publications (Key publications marked ****):
1. ****Akimoto T, Sorg BS, and Yan Z. Real-time imaging of peroxisome proliferator activated receptor γ co-activator-1α promoter activity in skeletal muscles of living mice. Am J Physiol 2004; 287(3):C790-6. Full text (PDF)

2. Rosenberg PB, Hawkins A, Stiber J, Shelton JM, Hutcheson K, Bassel-Duby R, Yan Z, Shin DM, and Williams RS. TRPC3 channels confer cellular memory of recent neuromuscular activity. Proc Natl Acad Sci 2004; 101(25):9387-92. Full text (PDF)

3. Akimoto T, Ribar TJ, Williams RS, and Yan Z. Skeletal muscle adaptation in response to voluntary running in Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) deficient mice. Am J Physiol 2004; 287(5):C1311-9. Full text (PDF)

4. Waters RE, Rotevatn S, Li P, Annex BH, and Yan Z. Voluntary Running Induces Fiber Type-Specific Angiogenesis in Mouse Skeletal Muscle. Am J Physiol 2004; 287(5):C1342-8. Full text (PDF)

5.**** Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z. Exercise stimulates PGC-1α transcription in skeletal muscle through activation of the p38 MAPK pathway. J. Biol. Chem. 2005; 280(20):19587-93. Full text (PDF)

6. Koves TR, Li P, Akimoto T, An J, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM. PGC-1α-mediated metabolic remodeling of skeletal muscle mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J. Biol. Chem. 2005; 280(39):33588-98. Full text (PDF)

7. Choi S, Liu X, Li P, Akimoto T, Lee SY, Gumbs C, Zhang M, Yan Z. Transcriptional profiling in mouse skeletal muscle following a single bout of voluntary running: evidence of increased cell proliferation. J. Appl. Physiol. 99(6):2406-15, 2005. Full text (PDF)

8. Jeftinija DM, Hebert SL, Norris CM, Wang QB, Yan Z, Rich MM, and Kraner SD. The CaV 1.2 Ca2+ channel is expressed in the sarcolemma of type I and IIa skeletal muscle fibers. Muscle & Nerve 2007; 36(4):482-90. Full text (PDF)

9. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, LeBrasseur NK, Yan Z, Spiegelman BM, Skeletal muscle fiber-type switching, exercise intolerance and myopathy in PGC-1? muscle-specific knockout animals, J. Biol. Chem 2007; 282(41):30014-21. Full text (PDF)

10. Wooldridge AA, Fortner CN, Lontay B, Akimoto T, Neppl RL, Facemire C, Datto MB, Kwon A, McCook E, Li P, Wang S, Thresher RJ, Miller SE, Perriard JC, Gavin TP, Hickner RC, Coffman TM, Somlyo AV, Yan Z, Haystead TA. Deletion of the PKA/PKG target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle. J. Biol. Chem 283:11850-9, 2008. Full text (PDF)

11. ****Akimoto T, Li P, Yan Z. Functional interaction of regulatory factors with the Pgc-1? promoter in response to exercise by in vivo imaging. Am. J. Physiol. Cell Physiol 295(1):C288-92, 2008. Full text (PDF)

12. Sun B, Youngi SP, Li P, Di C, Brown T, Salva MZ, Li S, Bird A, Yan Z, Auten R, Hauschka SD, Koeberl DD. Correction of Multiple Striated Muscles in Murine Pompe Disease Through Adenoassociated Virus-Mediated Gene Therapy. Mol Therapy 16:1366-71, 2008. Full text (PDF)

****Pogozelski1 AR, Geng T, Li P, Yi X1, . Lira VA, Zhang M, Chi J, Yan Z. p38γ mitogen-activated protein kinase is a key regulator in skeletal suscle metabolic adaptation in mice. PLoS One 4(11): e7934, 2009. Full text (PDF)

14. ****Geng T, Li P, Okutsu M, Yin X, Kwek J, Zhang M, Yan Z. 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. 2010, 298(3):C572-9, PMID: 20032509 link

15. Zechner C, Lai L, Zechner JF, Geng T, Yan Z, Rumsey JW, Collia D, Chen Z, Wozniak DF, Leone TC, Kelly DP. Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab. 2010 Dec 1;12(6):633-42. PubMed PMID: 21109195; PubMed Central PMCID: PMC2999961.

16. Baltgalvis KA, Call JA, Cochrane GD, Laker RC, Yan Z, Lowe DA. Exercise Training Improves Plantarflexor Muscle Function in mdx Mice. Med Sci Sports Exerc. 2012 Mar 28. [Epub ahead of print] PMID: 22460476 Link

17. Haldar SM, Jeyaraj D, Anand P, Zhu H, Lu Y, Prosdocimo DA, Eapen B, Kawanami D, Okutsu M, Brotto L, Fujioka H, Kerner J, Rosca MG, McGuinness OP, Snow RJ, Russell AP, Gerber AN, Bai X, Yan Z, Nosek TM, Brotto M, Hoppel CL, Jain MK. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation.Proc Natl Acad Sci U S A. 2012 Apr 9. [Epub ahead of print] PMID: 22493257 Link

18. 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. A PGC-1α Isoform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy. Cell. 2012 Dec 7;151(6):1319-31. doi: 10.1016/j.cell.2012.10.050. PubMed PMID: 23217713; PubMed Central PMCID: PMC3520615. Link

19. Meng ZX, Li S, Wang L, Ko HJ, Lee Y, Jung DY, Okutsu M, Yan Z, Kim JK, Lin JD. Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation. Nat Med. 2013 May;19(5):640-5. Link

20. Rowe GC, Patten IS, Zsengeller ZK, El-Khoury R, Okutsu M, Bampoh S, Koulisis N, Farrell C, Hirshman MF, Yan Z, Goodyear LJ, Rustin P, Arany Z. Disconnecting Mitochondrial Content from Respiratory Chain Capacity in PGC-1-Deficient Skeletal Muscle. Cell Rep. 2013 May 30;3(5):1449-56.
21. ****Lira VA, Okutsu M, Zhang M. Greene NP, Laker RC,Breen DS, Hoehn KL, Yan Z. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 2013 Oct;27(10):4184-93.

. ****Laker RC, Xu P, Ryall KA, Sujkowski A, Kenwood BM, Chain KH, Zhang M, Royal MA, Hoehn KL, Dirscoll M, Adler PN, Wessells RJ, Saucerman JJ, Yan Z. A novel MitoTimer reporter gene for mitochondrial content, structure, stress and damage in vivo. J Biol Chem. 2014 Mar 18. [Epub ahead of print] PubMed PMID: 24644293.

23. Lee HY, Gattu AK, Camporez JP, Kanda S, Guigni B, Kahn M, Zhang D, Galbo T, Birkenfeld AL, Jornayvaz FR, Jurczak MJ, Choi CS, Yan Z, Williams RS, Shulman GI, Samuel VT. Muscle-specific activation of Ca2+/calmodulin-dependent protein kinase IV increases whole-body insulin action in mice. Diabetologia. 2014 Apr 11. [Epub ahead of print] PubMed PMID: 24718953.

24. Drake JC, Wilson RJ, Yan ZMolecular mechanisms for mitochondrial adaptation to exercise training in skeletal muscle. FASEB J. 2015. PubMed PMID: 26370848. 

25. Call JA, Wilson RJ, Laker RC, Zhang M, Kundu M, Yan ZUlk1-mediated autophagy plays an essential role in mitochondrial remodeling and functional regeneration of skeletal muscle. Am J Physiol Cell Physiol. 2017 Jun 1;312(6):C724-C732. PubMed PMID: 28356270; PubMed Central PMCID: PMC5494591.

26. Yan Z, Kronemberger A, Blomme J, Call JA, Caster HM, Pereira RO, Zhao H, de Melo VU, Laker RC, Zhang M, Lira VA. Exercise leads to unfavourable cardiac remodelling and enhanced metabolic homeostasis in obese mice with cardiac and skeletal muscle autophagy deficiency. Sci Rep. 2017 Aug 11;7(1):7894. PubMed PMID: 28801668; PubMed Central PMCID: PMC5554260.

27. ****Laker RC, Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA, Fisher CC, Zhang M, Saucerman JJ, Goodyear LJ, Kundu M, Yan ZAmpk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun. 2017 Sep 15;8(1):548. PubMed PMID: 28916822; PubMed Central PMCID: PMC5601463. 

28. ****Wilson RJ, Drake JC, Cui D, Zhang M, Perry HM, Kashatus JA, Kusminski CM, Scherer PE, Kashatus DF, Okusa MD, Yan ZConditional MitoTimer reporter mice for assessment of mitochondrial structure, oxidative stress, and mitophagy. Mitochondrion. 2017 Dec 20. pii: S1567-7249(17)30196-4. PubMed PMID: 29274400.

1. Yan Z, Li P, and Akimoto T. Transcriptional control of the Pgc-1α gene in skeletal muscle. Exerc Sport Sci Rev 35(3):97-101, 2007.

2. Yan Z. Exercise, PGC-1α and metabolic adaptation in skeletal muscle. Appl Physiol Nutr Metab 34(3):424-7, 2009. Full text (PDF)

3. Lira V, Benton CR, Yan Z, Bonen A, PGC-1a regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab. 2010 Aug;299(2):E145-61. PubMed PMID: 20371735; PubMed Central PMCID: PMC2928513. Full text (PDF)

4. ****Yan Z, Okutsu M, Akhtar YN, Lira VA. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. J Appl Physiol (1985). 2011 Jan;110(1):264-74. PubMed PMID: 21030673.Link

5. ****Yan Z, Lira VA, Greene NP. Exercise training-induced regulation of mitochondrial quality. Exerc Sport Sci Rev. 2012 Jul;40(3):159-64. Link
Book Sections
1. Booth FW, Carson JA, Yan Z. Biochemistry of Exercise IX. Maughan RJ, Shirreffs SM, editors. Champaign, IL: Human Kinetics; 1996. Molecular and cellular adaptations of muscle in response to exercise. 339-44p.

2. Yan Z, Williams RS. Principles of Molecular Medicine . 2nd ed. Marschall SR, Patterson C, editors. Totowa, NJ: Humana Press; 2006. Skeletal muscle hypertrophy and response to training. 688-92p.