This study proposes to investigate the influence of Myostatin (Mst) on skeletal muscle plasticity. Mst is a member of a superfamily of transforming growth factor beta (TGF-2), a negative regulator of skeletal muscle mass, modulates transcription of muscle-specific genes, keeps muscle progenitor (satellite) cells in a quiescent state, inhibits muscle regeneration, and inhibits proliferation and differentiation of myoblasts, and downregulates DNA and protein synthesis. Mst expression has been detected in prenatal and postnatal muscle, but it is not fully understood whether Mst regulates muscle mass during embryogenesis or in adulthood. ? ? The overarching hypothesis for this study is that Mst plays a role in plasticity and physiological performance in adult skeletal muscle particularly in the context of pathological changes in muscle hypertrophy. This hypothesis will be tested using a compensatory overload model, in which the bilateral synergist ablation of the plantaris muscle will be performed. We propose that 1) inactivation of the Mst gene will further enhance the overload-induced hypertrophy; and 2) overexpression of Mst both during embryogenesis and adulthood will prevent the overload-induced muscle hypertrophy, albeit through on a different mechanism. We will provide evidence that the structural and physiological changes in muscle (such as fiber type composition, muscle power, force velocity characteristics and metabolic status) are induced by Mst in coordination with other atrophy/hypertrophy signaling pathways, notably through a negative feedback mechanism on p38 MAPK. Three different experimental animal models will be used: Mst knock out (KO), Mst overexpressing transgenic (Tg), and conditional Mst overexpressing transgenic (CMOT) mice. ? ? Three specific aims will allow us to explore the mechanisms by which Mst regulates muscle plasticity and performance:
Specific Aim 1. To determine the role of Mst in the genesis of muscle hypertrophy in Mst KO, Tg and CMOT animals, using a mechanical overload paradigm...
Specific Aim 2. To analyze muscle structural and functional changes induced by Mst and mechanical overloading.
Specific Aim 3. To investigate the molecular pathways involved in Mst regulation of muscle plasticity and adaptation. ? ? ?
