MOLECULAR BASIS OF MUSCLE RESPONSE TO PASSIVE STRETCH

众所周知，心肌和骨骼肌细胞都会对 通过开发快速自适应 机制包括代谢、结构上的明显变化 和生理特征。很有特色的模型 慢背阔肌(ALD)的纹状肌肥大 由非侵入性的肌肉拉伸引起的，如在心脏 肥大，成熟纤维增大，慢变明显。 肌球蛋白亚型和胚胎事件的重现导致 快速型和室型肌球蛋白异构体的出现。这一机制 负责这些变化及其与改变的功能的关联性 肥大的肌肉仍不清楚。最近在我们的研究中发现 其他被抑制的心肌肌球蛋白光表达的实验室 肥厚型酒精性肝病中MLC-2的表达及临床意义 正性和负性调节蛋白因子在 基因表达调控为检验这一假说提供了一个框架 ALD中现有肌核的重新编程是由于一种特定的 核蛋白因子对刺激反应的化学计量学。 从概念上讲，MLC-2表达的抑制是主动控制的 肌萎缩侧索硬化症的肌肉可以通过负值的损失来关闭 因子(S)来自功能转录复合体(ES)。这 我们的观察支持了这一假说，即心脏抑制 骨骼肌中的MLC-2是通过负性元件及其 结合蛋白。因此，我们的目标是：(I)确定和 描述假定的监管因素，(2)评估它们在 目标基因的沉默和激活，(Iii)建立 这些蛋白质因子水平的特定调节发生在 ALD肥厚的发生和(Iv)检测心脏MLC-2 有助于骨骼结构和/或功能的改变 肥厚的ALD中的肌纤维。这些目标的实现 有望让我们更好地了解肌肉细胞 对生理和病理生理应激的适应性。

It is well recognized that both cardiac and skeletal muscle cells respond to increasing functional demands by developing a rapid adaptational mechanism which includes distinct alterations in metabolic, structural and physiological characteristics. The well characterized model of striated muscle hypertrophy of the slow anterior latissimus dorsi (ALD) induced by a non-invasive stretch of the muscle involves, as in cardiac hypertrophy, enlargement of mature fibers, distinct transition in slow myosin isoforms and recapitulation of embryonic events resulting in the appearance of the fast and ventricular myosin isoforms. The mechanism responsible for these changes and their relevance to altered functions of the hypertrophied muscle remain unknown. The recent finding in our laboratory on expression of otherwise repressed cardiac myosin light chain-2 (MLC-2) in hypertrophied ALD together with the observation that positive and negative regulatory protein factors play a pivotal role in regulation of gene expression provide a framework to test the hypothesis that reprogramming of existing myonuclei in ALD occurs due to a specific stoichiometry of the nuclear proteins factors in response to stimulus. Conceptually, repression of MLC-2 expression is actively controlled in ALD muscle which can be switched off through the loss of a negative factor(s) from the functional transcriptional complex(es). This hypothesis received support by our observation that repression of cardiac MLC-2 in skeletal muscle is mediated through a negative element and its binding proteins. Our objectives, therefore, are: (i) to identify and characterize the putative regulatory factors, (ii) assess their roles in silencing and activation of the target gene, (iii) establish that specific modulations in levels of these protein factors occur during development of hypertrophy in ALD and (iv) test whether cardiac MLC-2 contributes to the altered structure and/or function of skeletal myofibers in hypertrophied ALD. The accomplishment of these objectives promises to lead us to a greater understanding of muscle cell adaptability to physiological and pathophysiological stresses.