Our long term goal is to develop novel therapies for skeletal muscle disorders. Current research in our laboratory is focused on the following three aspects of skeletal muscle biology.
1. Skeletal Muscle Wasting: Loss of skeletal muscle mass is a debilitating complication of several conditions (e.g. denervation, immobility, unloading zero gravity space travel, and aging) and disease states (e.g. cancer, diabetes, heart failure, etc.). One of the major areas of our research is to understand the trigging mechanisms and initial signaling events which lead to the loss of skeletal muscle in different catabolic conditions. Our studies have led to the identification of TWEAK-Fn14 system as a major mediator of skeletal muscle wasting. In addition to inhibiting myogenic differentiation and regeneration, TWEAK has been found to induce proteolysis in skeletal muscle especially in disuse conditions. TWEAK’s action is mediated in a manner which is quite novel for cytokines. Expression of the TWEAK receptor Fn14 and not the cytokine itself is increased in skeletal muscle upon denervation, demonstrating an “inside-out” signaling pathway; the receptor up-regulation allows for TWEAK activation of nuclear factor kappa B, causing an increase in the expression of the E3 ubiquitin ligase MuRF1, and atrophy. We are now focusing our studies to understand the mechanisms which stimulate the expression of Fn14 in skeletal muscle in the conditions of atrophy. We are also investigating how TWEAK affects the expression of various micro RNAs (miRs) and the role those miRs plays in TWEAK-induced muscle wasting.
2. Skeletal Muscle Development and Regeneration: Myogenesis is a multi-step process that is required not only for embryonic development but also for postnatal growth and repair of injured myofibers. Impairment in myogenesis is a critical determinant of skeletal muscle-wasting in chronic disease states and also for development of rhabdomyosarcoma in children. We are investigating signaling mechanisms which regulate the survival, proliferation, and differentiation of muscle progenitor cells (satellite cells) during muscle development and in response to injury. We are focusing to investigate the role of various TNF receptor-associated factors (TRAFs) and their interacting proteins in myogenesis. Moreover, we are interested to understanding the role of various inflammatory mediators in skeletal muscle regeneration and/or degeneration in vivo.
3. Pathophysiological Mechanisms in Muscular Dystrophy: Another important area of research in our laboratory is to understand the pathophysiological mechanisms and to identify novel molecules/drugs which can be used for the treatment of muscular dystrophy patients. In the past, we have reported aberrant regulation of several cell signaling pathways and transcription factors in skeletal muscle of dystrophin-deficient mdx mice. The present focus of our research is to investigate the mechanisms leading to extracellular matrix (ECM) breakdown and insufficient muscle regeneration in animal models of muscular dystrophy with special emphasis on the role of matrix metalloproteinases (MMPs). Our recent studies have suggested that the expression of several MMPs is aberrantly regulated in dystrophic muscle of mdx mice. We have also obtained initial evidence that the inhibition of MMPs using pharmacological or genetic approaches attenuates ECM abnormalities and disease progression in mdx mice. We are developing novel genetic mouse models to further investigate the role and the mechanism of action of various MMPs in pathogenesis of muscular dystrophy.
Hindi SM, Tajrishi M, and Kumar A (2013). Signaling mechanisms in mammalian myoblast fusion. Science Signaling, 6, re2 (1-9). (Previewed on the cover page of the journal).
Shin J, Tajrishi M, Ogura Y, and Kumar A (2013). Wasting mechanisms in muscular dystrophy. International Journal of Biochemistry & Cell Biology, (in press; Online PMID: 23669245)
Hindi SM, Shin J, Ogura Y, Li H, and Kumar A (2013). Matrix metalloproteinase-9 inhibition improves proliferation and engraftment of myogenic cells in dystrophic muscle of mdx mice. PLOS One (in press).
Sato S, Ogura Y, Mishra V, Shin J, Bhatnagar S, Hill BG, and Kumar A (2013) TWEAK promotes exercise intolerance by decreasing skeletal muscle oxidative phosphorylation capacity. Skeletal Muscle, 3: 18.
Hindi SM, Paul PK, Dahiya S, Bhatnagar S, Mishra V, Choi Y, and Kumar A (2012). Reciprocal interaction between TRAF6 and Notch Signaling regulates regeneration of adult myofibers upon injury. Molecular and Cellular Biology, 32: 4833-4845
Kumar A, Bhatnagar S, and Paul PK (2012) TWEAK and TRAF6 regulate skeletal muscle atrophy. Current Opinion in Clinical Nutrition and Metabolic Care 15:233-239.
Paul PK, Bhatnagar S, Mishra V, Srivastava S, Darnay BG, Choi Y, and Kumar A (2012). The E3 ubiquitin ligase TRAF6 intercedes in starvation-induced skeletal muscle atrophy through multiple mechanisms. Molecular and Cellular Biology 32:1248-1259.
Dahiya S, Bhatnagar S, Hindi SM, Jiang C, Paul PK, Kuang S, and Kumar A (2011) Elevated levels of active matrix metalloproteinase-9 cause hypertrophy in skeletal muscle of normal and dystrophin-deficient mdx mice. Human Molecular Genetics, 20: 4345-4359.
Dahiya S, Givvimani S, Bhatnagar S, Qipshidze N, Tyagi SC, and Kumar A (2011). Osteopontin-stimulated expression of matrix metalloproteinase-9 causes cardiomyopathy in the mdx model of Duchenne muscular dystrophy. Journal of Immunology, 187:2723-2731
Paul PK, Gupta SK, Bhatnagar S, Panguluri SK, Darnay BG, Choi Y, Kumar A (2010). Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice. Journal of Cell Biology, 191, 1395-1411. Editorial in Science Signaling- “Understanding Atrophy”
Mittal A, Bhatnagar S, Kumar A, Paul PK, Kuang S, and Kumar A (2010). Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice. American Journal of Pathology, 177, 1732-1742.
Waddell JN, Zhang P, Wen Y, Gupta SK, Yevtodiyenko A, Schmidt JV, Bidwell CA, Kumar A, and Kuang S (2010). Dlk1 is necessary for proper skeletal muscle development and regeneration. PLoS One, 5(11):e15055.
Mittal A, Bhatnagar S, Kumar A, Lach-Trifilieff E, Wauters S, Li H, Makonchuk DY, Glass DJ, and Kumar A (2010).The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. Journal of Cell Biology, 188, 833-849. Editorial in Science Signaling- “TWEAKing Muscle Atrophy”
Kumar A, Bhatnagar S, and Kumar A (2010).Matrix metalloproteinase inhibitor batimastat alleviates pathology and improves skeletal muscle function in dystrophin-deficient mdx mice. American Journal of Pathology, 177, 248-260.
Bhatnagar S, Kumar A, Makonchuk DY, Li H, and Kumar A (2010). Transforming growth factor-b activated kinase 1 (TAK1) is an essential regulator of myogenic differentiation. Journal of Biological Chemistry, 285,6401-6411.
Panguluri SK, Bhatnagar S, Kumar, A., McCarthy JJ, Srivastava AK, Cooper NG, Lundy RF, and Kumar A (2010). Genomic profiling of messenger RNA and micro RNA reveals novel mechanisms of TWEAK-mediated skeletal muscle wasting in mice. PLOS One, 5 (1):e8760.
Bhatnagar S and Kumar A (2010). Therapeutic targeting of signaling pathways in muscular dystrophy. Journal of Molecular Medicine, 88, 155-166.
Li H, Mittal A, Makonchuk DY, Bhatnagar S, and KumarA (2009). Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy. Human Molecular Genetics, 18, 2584-2598.
Kumar M, Makonchuk DY, Li H, Mittal A, and Kumar A (2009) Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) activates proinflammatory signaling pathways and gene expression through the activation of TGF-beta activated kinase 1. Journal of Immunology, 182, 2439-2448.
Li H, Mittal A, Paul PK, Kumar M, Shrivastava DS, Tyagi SC, and Kumar, A. (2009) Tumor Necrosis Factor-Related Weak Inducer of Apoptosis (TWEAK) augments matrix Metalloproteinase-9 production (MMP-9) in skeletal muscle through the activation of nuclear factor-kappa B-inducing kinase and p38 mitogen-activated protein kinase: a potential role of MMP-9 in myopathy. Journal of Biological Chemistry, 284, 4439-4450.
Li H, Malhotra S, and Kumar A (2008) Nuclear factor-kappa B signaling in skeletal muscle atrophy.Journal of Molecular Medicine, 86, 1113-1126.
Dogra C, Changotra H, Wedhas N, Wergedal JE, and Kumar A (2007) TNF-Related Weak inducer of Apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. FASEB Journal, 21, 1857-1869.
Srivastava AK, Wedhas N, Arnush M, Chadwick RB, Linkhart TA, and Kumar A (2007) Tumor necrosis factor-alpha augments matrix metalloproteinase-9 production in skeletal muscle cells through the activation of transforming growth factor-beta-activated kinase 1 (TAK1)-dependent signaling pathway. Journal of Biological Chemistry, 282, 35113-35124.
Dogra C, Hall SL, Wedhas N, Linkhart TA, and Kumar A (2007) Fibroblast growth factor inducible-14 (Fn14) is required for the expression of myogenic regulatory factors and differentiation of myoblasts into myotubes: Evidence for TWEAK-independent functions of Fn14 during myogenesis. Journal Biological Chemistry, 282, 15000-15010.