Genetics of Vertebrate Skeletal Muscle Development, Differentiation, Stem Cell-mediated Regeneration and Disease

The vertebrate skeletal muscle is crucial to locomotion, posture, and metabolism among other functions. The adult skeletal muscle is made up of muscle fibers (myofibers), connective tissue (connective tissue and connective tissue fibroblasts) and the muscle stem cells (satellite cells). The myofibers are elongated, multinucleate cells that are the contractile units of the skeletal muscle, formed during development by fusion of myoblasts. The connective tissue connects the muscles to tendon and bone, forms an important component of the niche within which the myofibers and muscle stem cells reside and transmits the force of muscle contraction. The satellite cells are quiescent stem cells which are activated during muscle injury or disease and are crucial to muscle regeneration. Previously, our work on the mammalian skeletal muscle connective tissue fibroblasts identified the Wnt/beta-Catenin pathway transcription factor Tcf4 as the first marker for these fibroblasts and using mouse genetic experiments and in vitro co-cultures that Tcf4 and the muscle connective tissue fibroblasts are crucial for proper muscle maturation, differentiation and function.

The skeletal muscle fibers have distinct metabolic and contractile properties based on their function and location. Myofibers can be 'slow' (slow contracting, utilizing oxidative metabolism and slow to fatigue) or 'fast' (fast contracting, utilizing glycolytic metabolism and quick to fatigue). Muscles that are postural or are used for longer periods of time are generally rich in slow fibers whereas muscles that are used for short periods of time but require fast contraction are rich in fast fibers. Muscle fiber type is quite plastic and based on usage, fiber type in adults can convert from one to another. Skeletal muscle myosin heavy chains (MyHC) are the proteins that confer fiber type specific contractile properties to myofibers. There are mainly 6 MyHCs: MyHCI (slow), MyHCIIa, MyHCIIx/d, MyHCIIb (fast), MyHCembryonic and MyHCneonatal. MyHCIIa, MyHCIIx/d and MyHCIIb are expressed from neonatal stages and in the adult, MyHCI is expressed during development, neonatal stages and in the adult while MyHCembryonic and MyHCneonatal are normally expressed only during development and transiently during muscle injury or disease in the adult. I am currently trying to understand how skeletal muscle differentiation happens during embryonic development as well as during adult muscle regeneration after injury or disease using animal models and in vitro techniques.

• Wellcome-DBT Intermediate Fellow

• Masum Saini
  Young Investigator
  masum@rcb.ac.in
• Megha Agarwal
  Junior Research Fellow
  megha.agarwal@rcb.res.in
• Pankaj Kumar
  Junior Research Fellow
  pankaj.kumar@rcb.res.in
• Akashi Parashar
  Junior Research Fellow
  akashi.parashar@rcb.res.in
• Shreyasi Das
  Junior Research Fellow
  shreyasi@rcb.res.in
• Ankur Kumar
  Project Assistant
  ankur.kumar@rcb.res.in
• Anushree Balodi
  Junior Research Fellow
  anushree@rcb.res.in
• Slok Jindal
  Junior Research Fellow
  shlok@rcb.res.in
• Aakanksha Verma
  Project Assistant
  aakankasha@rcb.res.in

1. Agarwal M, Kumar P, Mathew SJ (2015)  The Groucho/Transducin-like enhancer of split protein family in animal development. IUBMB Life 67:472.
2. Keefe AC, Lawson JA, Flygare SD, Fox ZD, Colasanto MP, Mathew SJ, Yandell M, Kardon G. (2015) Muscle stem cells contribute to myofibres in sedentary adult mice. Nature Communications 14;6:7087 (Recommended by Faculty of 1000).
3. Mathew SJ, Rembold M, Leptin M. (2011) A role for Traf4 in polarizing adherens junctions as a prerequisite for efficient cell shape changes. Molecular and Cellular Biology 24:4978.
4. Murphy MM, Lawson JA, Mathew SJ, Hutcheson DA, Kardon G. (2011) Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138:3625-3637. (Featured article, Recommended by Faculty of 1000)
5. Mathew SJ. (2011) InACTIVatINg cancer cachexia. Dis Model Mech 4:283.
6. Mathew SJ, Hansen JM, Merrell AJ, Murphy MM, Lawson JA, Hutcheson DA, Hansen MS, Angus-Hill M, Kardon G. (2011) Connective tissue fibroblasts and Tcf4 regulate myogenesis. Development 138:371-384.
7. Mathew SJ, Haubert D, Kronke M, Leptin M. (2009) Looking beyond death: a morphogenetic role for the TNF signalling pathway. J Cell Sci 122:1939.
8. Mathew SJ, Kerridge S, Leptin M. (2009) A small genomic region containing several loci required for gastrulation in Drosophila. PLoS One 4:e7437