Skeletal Muscle Adaptation to Altered Environmental Demands

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Skeletal muscle contractions generate the forces that allow us to interact with our environment. The structural and functional characteristics of skeletal muscle fibres determine the nature and quality of those interactions. Interestingly, this post-mitotic tissue possesses the unique ability to change its structural and functional properties to meet new demands placed on it by the external environment. For example, chronic increases in activity lead to the conversion of a fast contracting (fast-twitch) muscle that fatigues rapidly into a slower contracting but fatigue resistant muscle. Conversely, inactivity or immobilisation induces fibre atrophy, muscle wasting and increased fatigability. There is a paucity of information regarding the events that underlie the structural and functional plasticity of skeletal muscles, especially with regard to the type and magnitude of contributions made by an endogenous population of pre-mitotic muscle stem cells (satellite cells). To investigate this, we use a rodent model of muscle training in which Chronic Low-Frequency electrical Stimulation (CLFS) is applied to a fast-twitch muscle to convert it into a slower phenotype. The capacity of this experimental model to demonstrate the full adaptive potential of skeletal muscle, without causing muscle injury, is unparalleled. When combined with cell culture experimental models, it allows us to further isolate specific signaling pathways, individual molecules and epigenetic regulatory events in order to establish their individual and related contributions as determinants of skeletal muscle fibre phenotype. The outcomes of this research will advance our fundamental understanding of the cellular and molecular adaptive strategies used by skeletal muscle.RESEARCH OBJECTIVES:LONG-TERM RESEARCH PROGRAM OBJECTIVE:To conduct hypothesis-driven research that reveals cellular and molecular strategies used by skeletal muscle to adapt to altered environmental demands.SHORT-TERM RESEARCH PROGRAM OBJECTIVES:(1) To investigate the epigenetic determination of a fast satellite cell lineage in vivo.(2) To determine patterns of epigenetic programming in response to muscle exercise in vivo and in vitro.(3) To investigate fibre type determination by calcineurin and Nuclear Factor of Activated T-cell (NFAT) isoforms in vitro.A principal feature of this research will be the effective mentorship and training of Highly Qualified Personnel (HQP) at all levels. The proposed program has the potential for significant scientific discoveries that reveal how muscle fibre phenotypes are epigenetically regulated, particularly within the satellite cell population. It will provide HQP's the opportunity to discover quantitative and qualitative aspects of epigenetic control within in vivo and in vitro physiological models that have a high probability of being conserved across vertebrate species.