In response to work overload, post-mitotic adult muscle cells hypertrophy and express an isomyosin that is bioenergetically more favorable. However, in spite of this important physiological adaptation, little is known about the transcriptional regulation of the genes involved in this isomyocin transition. The long-term objective of this proposal is to identify the inducible cis-element(s) necessary for this adaptive response using slow myosin light chain one (SMLC1) genes as a model system. Initial experiments will involve generating transgenic mice harboring different SMLC1CAT genes with the subsequent determination of tissue specific and inducible expression patterns. Upon localization of an inducible cis- element(s) to a region of the SMLC1 promoter, mobility and footprinting assays will be performed to resolve the exact binding motif required for induciton of the SMLC1 gene during work overload. The use of this model system will ultimately lead to a better understanding of the molecular mechanisms underlying muscle plasticity which may provide specific insight into the processes involved in various skeletal myopathies and more generally into cancer, as cancer is typically associated with an alteration in phenotype leading to a pathological state.
| McCarthy, J J; Vyas, D R; Tsika, G L et al. (1999) Segregated regulatory elements direct beta-myosin heavy chain expression in response to altered muscle activity. J Biol Chem 274:14270-9 |
