Assistant Professor The Brown Foundation Institute of Molecular Medicine, Center for Metabolic and Degenerative Disease
Areas of Interests
- Research Interest
- Transcriptional Regulation Of Skeletal Muscle Function
Transcriptional Regulation Of Skeletal Muscle Function
Skeletal muscle is a remarkably plastic tissue that adapts to environmental cues by undergoing changes in its metabolic and contractile properties. For example, endurance training (or exercise) increases slow-twitch myofibers that are rich in mitochondria, fat oxidizing enzymes and fatigue-resistant contractile proteins. This, in turn leads to improved aerobic capacity and energy efficiency at the physiological level. Conversely, loss of these myofibers is commonly linked to the pathology associated with physical immobilization, aging, diabetes and even certain type of muscular dystrophies underscoring the importance of muscular aerobic capacity in health. Despite the known benefits of increasing aerobic muscles, gene regulatory pathways that encode this fiber type remain unclear. Discovery of these pathways will have important therapeutic implications in metabolic and muscle degenerative diseases.
In our laboratory, we are particularly interested in understanding how nuclear receptors – that are hormone or drug-activated transcriptional factors – regulate metabolic and contractile properties of the skeletal muscle. Recently, we have identified a molecular interaction between serine/threonine kinase AMPK and nuclear receptor PPARd that can be pharmacologically targeted to activate genes linked to mitochondrial biogenesis, fatty acid oxidation, and slow-twitch contractile myofibers in skeletal muscles and improve exercise endurance. These finding reveal that exercise-activated kinases and nuclear receptors are key components of myocellular transcriptional machinery controlling metabolism and fatigue. We are currently investigating the role of estrogen receptor-related receptors (ERR) – a class of orphan nuclear receptors – in skeletal muscle. ERR’s and particularly ERRg is highly expressed in oxidative slow-twitch muscle fibers suggesting a role for these receptors in the regulation of aerobic metabolism. We have genetically targeted ERR’s to investigate the effect of skeletal muscle-specific receptor modification on myocellular gene expression, metabolism and fatigue. Furthermore, we are exploring the potential role of ERR’s in ameliorating diabetes and muscular dystrophy. Other ongoing projects in the lab apply the aforementioned candidate approach to study additional orphan nuclear receptors as well as use genomics and proteomics to identify novel receptor interacting partners and gene targets in skeletal muscle.
Students and post-doctoral trainees will exploit transgenic, knockout and adenoviral gene delivery technology for targeting nuclear receptors in the skeletal muscle. The trainees will gain experience in using genetic mouse models, cell culture, immuno-histochemistry, real-time PCR and microarray analysis along with biochemistry, molecular biology and pharmacology to study mechanisms of receptor signaling. They will also use affinity purification in conjugation with mass spectrophotometry, and ChIP-CHIP analysis to discover receptor interacting proteins and genome-binding sites, respectively. Additionally, metabolic cages, treadmill and voluntary running wheels will be employed to investigate the physiological impact of muscle-specific receptor modulation.
- Matsakas A, Yadav V, Lorca S, Narkar V. (2013) Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming. FASEB J. 27(10): 4004-4016.
- Chao LC, Wroblewski K, Ilkayeva OR, Stevens RD, Bain J, Meyer GA, Schenk S, Martinez L, Vergnes L, Narkar VA, Drew BG, Hong C, Boyadjian R, Hevener AL, Evans RM, Reue K, Spencer MJ, Newgard CB, Tontonoz P. (2012) Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization. J Lipid Res. 53(12): 2610-9.
- Matsakas A, Yadav V, Lorca S, Evans RM, Narkar VA. (2012) Revascularization of Ischemic Skeletal Muscle by Estrogen-Related Receptor-γ. Circulation Research. 110(8): 1087-96.
- Matsakas A, Macharia R, Otto A, Elashry MI, Mouisel E, Romanello V, Sartori R, Amthor H, Sandri M, Narkar V, Patel K. (2012) Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse. Experimental Physiology. 97(1): 125-40.
- Narkar VA, Fan W, Downes M, Yu RT, Jonker JW, Alaynick WA, Banayo E, Karunasiri MS, Lorca S, Evans RM. (2011) Exercise and PGC-1α-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERRγ. Cell Metabolism. 13(3): 283-93
- Matsakas A, Narkar VA. (2010) Endurance exercise mimetics in skeletal muscle. Curr Sports Med Rep. 9(4): 227-32.
- Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H, Kang H, Shaw RJ, Evans RM. (2008) AMPK and PPARdelta agonists are exercise mimetics. Cell. 134(3): 405-15.
- Barish GD, Narkar VA, Evans RM. (2006) PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest. 116(3): 590-7.
- Szanto A, Narkar VA, Shen Q, Uray IP, Davies PJ, Nagy L. (2004) Retinoid X receptors: X-ploring their (patho)physiological functions. Cell Death Differ. 11 Suppl 2: S126-43.
- Trivedi M, Narkar VA, Hussain T, Lokhandwala MF. (2004) Dopamine recruits D1A receptors to Na-K-ATPase-rich caveolar plasma membranes in rat renal proximal tubules. Am J Physiol Renal Physiol. 287(5): F921-31.
- Narkar VA, Kunduzova O, Hussain T, Cambon C, Parini A, Lokhandwala MF. (2004) Dopamine D2-like receptor agonist bromocriptine protects against ischemia/reperfusion injury in rat kidney. Kidney Int. 66(2): 633-40.
- Narkar VA, Hussain T, Lokhandwala MF. (2002) Activation of D2-like receptors causes recruitment of tyrosine-phosphorylated NKA alpha 1-subunits in kidney. Am J Physiol Renal Physiol. 283(6): F1290-5.
- Narkar VA, Hussain T, Lokhandwala M. (2002) Role of tyrosine kinase and p44/42 MAPK in D(2)-like receptor-mediated stimulation of Na(+), K(+)-ATPase in kidney. Am J Physiol Renal Physiol. 282(4): F697-702.
- Narkar VA, Hussain T, Pedemonte C, Lokhandwala MF. (2001) Dopamine D(2) receptor activation causes mitogenesis via p44/42 mitogen-activated protein kinase in opossum kidney cells. J Am Soc Nephrol. 12(9): 1844-52.