Skeletal Muscle Adaptation to Altered Environmental Demands

骨骼肌收缩产生的力量使我们能够与环境互动。骨骼肌纤维的结构和功能特征决定了这些相互作用的性质和质量。有趣的是，这种有丝分裂后的组织具有改变其结构和功能特性的独特能力，以满足外部环境对其提出的新要求。例如，活动的慢性增加导致快速收缩（快速收缩）肌肉迅速疲劳转化为收缩较慢但抗疲劳的肌肉。相反，不活动或不活动会导致纤维萎缩、肌肉萎缩和疲劳增加。关于骨骼肌结构和功能可塑性的基础事件，特别是关于有丝分裂前肌肉干细胞（卫星细胞）的内源性群体所作贡献的类型和幅度的信息很少。为了研究这一点，我们使用了一个啮齿动物模型的肌肉训练，其中慢性低频电刺激（CLFS）被施加到一个快速收缩的肌肉，将其转化为一个较慢的表型。该实验模型在不引起肌肉损伤的情况下展示骨骼肌的全部适应潜力的能力是无与伦比的。当与细胞培养实验模型相结合时，它使我们能够进一步分离特定的信号通路，单个分子和表观遗传调控事件，以建立其作为骨骼肌纤维表型决定因素的个体和相关贡献。这项研究的结果将促进我们对骨骼肌所使用的细胞和分子适应策略的基本理解。 研究成果： 长期研究目标： 进行假设驱动的研究，揭示骨骼肌用于适应改变的环境需求的细胞和分子策略。 短期研究成果： (1)探讨体内快速卫星细胞谱系的表观遗传决定。 (2)确定表观遗传编程模式在体内和体外肌肉运动的反应。 (3)探讨钙调神经磷酸酶和活化T细胞核因子（NFAT）亚型在体外对纤维类型的判断。 这项研究的一个主要特点将是有效的指导和培训各级高素质人员（HQP）。该计划具有重大科学发现的潜力，揭示了肌纤维表型如何在表观遗传学上受到调节，特别是在卫星细胞群中。它将提供HQP的机会，发现定量和定性方面的表观遗传控制在体内和体外的生理模型，有很高的概率被保存在脊椎动物物种。

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.