Skeletal Muscle Adaptation to Altered Environmental Demands

骨骼肌适应改变的环境需求

• 批准号: RGPIN-2016-05180
• 负责人: Putman, Charles
• 金额: $ 2.26万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762193
• 关键词: Skeletal; Muscle; Adaptation; Altered; Environmental

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.

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的新要求。例如，活动的长期增加导致快速收缩（快速抽搐）肌肉迅速疲劳转化为缓慢收缩但抗疲劳的肌肉。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背后的事件的信息缺乏，特别是关于内源性有丝分裂前肌肉干细胞（卫星细胞）群体所作贡献的类型和程度。为了研究这一点，我们使用了一种啮齿动物肌肉训练模型，其中慢性低频电刺激（CLFS）应用于快速抽搐肌肉，将其转化为较慢的表型。这个实验模型展示了骨骼肌的完全适应潜力，而不会造成肌肉损伤，这是无与伦比的。当与细胞培养实验模型相结合时，它允许我们进一步分离特定的信号通路，个体分子和表观遗传调控事件，以确定它们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细胞和分子适应策略的基本理解。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。短期研究目标：(1)在体内研究快速卫星细胞谱系的表观遗传学决定。(2)确定体内和体外肌肉运动对表观遗传编程的响应模式。(3)探讨钙调磷酸酶和活化t细胞核因子（NFAT）异构体在体外测定纤维类型的方法。这项研究的一个主要特点将是有效指导和培训各级高素质人才。拟议的计划有可能产生重大的科学发现，揭示肌肉纤维表型是如何被表观遗传调节的，特别是在卫星细胞群体中。它将为HQP提供机会，在体内和体外生理模型中发现表观遗传控制的定量和定性方面，这些模型在脊椎动物物种中具有很高的保守性。