Myosin heavy chain (MyHC) is a quintessential marker of skeletal muscle fiber phenotype and function since it is a major determinate of muscle fiber maximum unloaded velocity of shortening (Vmax), Presently, little is known about how the integrative biological response to mechanical overload (MOV) leads to fiber-type shifts and altered transcriptional regulation of MyHC genes. Towards this end, our DNA-protein interaction and transgenic deletion/mutagenesis studies have defined a minimal betaMyHC promoter (-293/+120) that mimics the expression pattern of the endogenous betaMyHC gene during development and in response to MOV. These studies also identified a cis-acting element (beta A/T-rich; -269/-258) that is required for slow skeletal muscle expression and that serves a potential role in MOV-responsiveness of this minimal betaMyHC promoter. In a yeast 1-hybrid screen of an MOV muscle cDNA library we found that nominal transcription enhancer factor-/(NTEF-1) specifically binds the betaMyHC A/T-rich element despite previous observations that TEF proteins interacted solely at muscle-CAT (MCAT) elements. We showed that TEF proteins can transactivate a betaMyHC promoter and a betaA/-T-rich/thymidine kinase promoter in muscle cells. We also show that TEF protein binding extends to a subset of MEF2 and A/T-rich elements, and the palindromic Mt site, which was enriched only when using MOV nuclear extracts. Importantly, since TEF proteins regulate numerous muscle genes, we expect that our findings will have global relevance to the regulation of striated and smooth muscle gene networks under basal and hypertrophic conditions, and gene regulation in all TEF expressing cells. Thus, the major focus of this grant is to decipher the physiological role of the TEF proteins in regulating skeletal muscle phenotype by performing the following aims: 1) to study the phenotypic consequences of transgenic over expression of TEF-1 proteins targeted to striated muscle, 2) to isolate and study muscle specific TEF interacting proteins by yeast 2-hybrid and classical proteomics, and 3) to confirm the in vivo function of NTEF-1 by generating transgenic knock-out mice. Northern and western analyses will assess the impact of TEF-1 protein over expression or deletion on whole muscle phenotype, which will be correlated to whole muscle and single fiber functional analysis. This work is expected to identify potential protein targets for therapies aimed at providing countermeasures against altered muscle phenotype and debilitating loss of function induced by altered mechanical loads resulting from disease, space flight or extended bed rest.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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University of Missouri-Columbia
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Southard, Sheryl; Kim, Ju-Ryoung; Low, SiewHui et al. (2016) Myofiber-specific TEAD1 overexpression drives satellite cell hyperplasia and counters pathological effects of dystrophin deficiency. Elife 5:
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