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.
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| Dhar, M; Mascareno, E M; Siddiqui, M A (1997) Two distinct factor-binding DNA elements in cardiac myosin light chain 2 gene are essential for repression of its expression in skeletal muscle. Isolation of a cDNA clone for repressor protein Nished. J Biol Chem 272:18490-7 |
