Mitochondiral Biogenesis

p38 MAPK in exercise-induced mitochondrial biogenesis

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 the Yan Lab has focused on mitochondrial biogenesis and mitophagy in skeletal muscle. The lab's 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). The lab has recently developed a novel mitochondrial reporter gene, MitoTimer, and inducible MitoTimer reporter mice for assessing mitochondrial content, size, oxidative stress and mitophagy in vivo. The lab's more recent work revealed that exercise training promotes mitophagy. The team now studies the regulation and functional importance of exercise training-induced mitophagy in metabolic and contractile adaptations.

Publications

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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

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

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. Link

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.

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

Reviews

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.

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

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.

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