Areas of Interest

Research Interests

骨骼肌功能的转录调节

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骨骼肌功能的转录调节

骨骼肌是一种非常出色的塑料组织，通过发生代谢性和收缩特性的变化来适应环境线索。例如，耐力训练（或运动）增加了富含线​​粒体，脂肪氧化酶和抗疲劳的收缩蛋白的慢扭转肌纤维。这反过来又可以提高生理水平的有氧能力和能源效率。相反，这些肌纤维的丧失通常与与物理固定，衰老，糖尿病甚至某些类型的肌营养不良的病理有关，强调了肌肉有氧运动能力在健康中的重要性。尽管有氧肌肉增加了已知的好处，但编码这种纤维类型的基因调节途径尚不清楚。这些途径的发现将在代谢和肌肉退行性疾病中具有重要的治疗意义。

在我们的实验室中,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.

Publications

Publication Information

  • 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）骨骼肌NUR77表达增强了氧化代谢和底物利用。J脂质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）锻炼训练减轻了超肌表型，并恢复肌生抑素无效小鼠中的骨骼肌功能。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和Ppardelta激动剂是运动模仿。Cell.134（3）：405-15。
  • Barish GD,Narkar VA，Evans RM。（2006）PPAR三角洲：代谢综合征中心的匕首。J Clin Invest.116(3): 590-7.
  • Szanto A,Narkar VA，Shen Q，Uray IP，Davies PJ，Nagy L.（2004）类视黄素X受体：X-PLON-PLECHONS（PATHO）生理功能。Cell Death Differ.11补充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）D2样受体的激活导致肾脏中酪氨酸磷酸化的NKA Alpha 1-亚基在肾脏中募集。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.