Novel Roles for Satellite Cells in Adult Skeletal Muscle Adaptation

 描述（由申请人提供）：根据目前的奖项，我们已经获得了令人兴奋的新证据，卫星细胞是必要的适当重塑细胞外基质在肥大。我们报道了在卫星细胞耗竭的肌肉中，纤维化显著增加，这与钝化的长期肥大反应有关。我们的初步数据表明，激活的卫星细胞/肌源性祖细胞（MPC）能够通过外泌体递送microRNA抑制成纤维细胞合成细胞外基质成分。我们推测，卫星细胞的丢失消除了这个“刹车”，导致胶原蛋白和纤维化的过度生产，最终限制了长期的肥大性生长。我们进一步假设，纤维化作为损失的结果， 卫星细胞优先限制快肌纤维的生长，而慢肌纤维的生长受肌纤维结构域大小的限制。因此，快速纤维显示出相对灵活的肌层结构域，而慢速纤维可能对卫星细胞的生长有更严格的要求。本提案的目的是使用遗传小鼠模型和体外细胞培养，通过追求以下目标来研究卫星细胞在骨骼肌适应中的这些新作用。目的1探讨骨骼肌肥大时卫星细胞调控细胞外基质重塑的机制。目的2将确定纤维化是否减轻卫星细胞耗竭肌肉的长期肥大，以及纤维类型组成的影响。目的3将确定是否有一个纤维类型特定的要求，在骨骼肌肥大的卫星细胞融合。我们已发表的工作和新的初步数据清楚地表明，我们对成人骨骼肌适应中卫星细胞功能的理解仍然不完整。本提案中描述的研究解决了我们知识中的这一根本差距，并有望提供更有效地评估卫星细胞作为治疗剂的使用所需的关键信息，以预防或恢复与营养不良，癌症，年龄和废用后康复相关的骨骼肌质量损失。

 DESCRIPTION (provided by applicant): Under the current award, we have acquired exciting new evidence that satellite cells are necessary for the proper remodeling of the extracellular matrix during hypertrophy. We reported that in muscle depleted of satellite cells there was a significant increase in fibrosis that was associated with a blunted long-term hypertrophic response. Our preliminary data show that activated satellite cells/myogenic progenitor cells (MPCs) are capable of repressing the synthesis of extracellular matrix components by fibroblasts through exosomal delivery of microRNAs. We hypothesize that the loss of satellite cells removes this "brake" leading to the over-production of collagen and fibrosis, ultimately limiting long-term hypertrophic growth. We further hypothesize that fibrosis as a result of loss of satellite cells preferentially limits growth in fast muscle fibers, whereas growth of slow fibers i limited by myonuclear domain size. Thus, fast fibers display a relatively flexible myonuclear domain, whereas slow fibers may have a more stringent requirement for satellite cells for growth. The objectives of this proposal are to use genetic mouse models and in vitro cell culture to investigate these novel roles for satellite cells in skeletal muscle adaptation by pursuing the following aims. Aim 1 will determine the mechanisms underlying satellite cell regulation of extracellular matrix remodeling during skeletal muscle hypertrophy. Aim 2 will determine if fibrosis attenuates long-term hypertrophy in satellite cell-depleted muscle, and the influence of fiber type composition. Aim 3 will determine if there is a fiber type-specific requirement for satellite cell fusion during skeletal muscle hypertrophy. Our published work and new preliminary data clearly show that our understanding of satellite cell function in adult skeletal muscle adaptation remains incomplete. The studies described in this proposal address this fundamental gap in our knowledge and are expected to provide critical information necessary to more effectively evaluate the use of satellite cells as a therapeutic agent to prevent or restore the los of skeletal muscle mass associated with dystrophies, cancer, age and rehabilitation following disuse.