In aging rodents and humans, decreased muscle mass does not fully account for the decrease in strength, indicating that atrophy only partially explains muscle weakness. Publications from our laboratory and others support the concept that aging impairs muscle activation-contraction efficiency. Altered transmittal of membrane depolarization to SR Ca2+ release decreases specific force in a process termed excitation- contraction uncoupling (ECU). Previous works from our laboratory identified the mouse specific Cav1.1 subunit gene 5'-flanking sequences necessary for basal transcription and control of Cav1.1 expression. However, the mechanism leading to impaired Cav1.1 transcription with aging and its treatment is unknown. Troponin T (TnT) is known to mediate the interaction between the Tn complex and tropomyosin (Tm) in the myoplasm, which is essential for calcium-activated striated muscle contraction. We have preliminary evidence of a nontraditional role for TnT3, the TnT isoform expressed in fast-twitch muscle fibers. We found full-length (FL)-TnT3 and its fragments in both the nuclear and cytosolic fractions of myofibers isolated from mouse skeletal muscle. More important, the myonuclei from old FVB mice had less of the full-length protein and more of the COOH-terminal (CT) fragment than those of young mice. When we knocked down endogenous TnT3 by shRNA in muscle in vivo, the calcium channel a1 subunit, essential molecule for muscle contraction, was down-regulated at both the RNA and protein levels. The following specific aims will test the hypotheses that: (1) TnT3 regulates voltage-gated Ca2+ channel ?1 subunit (Cav1.1) expression in fast adult myofibers, and (2) decreased nuclear FL-TnT3 and increased CT-TnT3 fraction result in decreased Cacna1 expression and impaired excitation-contraction coupling with aging. These hypotheses will be tested by the following specific aims. (1) To establish that TnT3 regulates Cav1.1 expression and excitation-contraction coupling. (2) To determine that TnT3 is enzymatically cleaved in aging skeletal muscle and (3) To determine whether inhibiting skeletal muscle ?- calpain prevents age-dependent increase in TnT3 fragmentation and reduced Cacna1 expression and sarcoplasmic reticulum Ca2+ release. The proposed studies will define a novel role for TnT3 as a regulator of Cav1.1 expression and a tool to ameliorate or prevent muscle weakness with aging.
Age-related deterioration of skeletal muscle performance is a leading cause of disability and morbidity in the elderly population worldwide. This project seeks to define the causes of impaired skeletal muscle mass force generation with age and to develop therapeutic strategies to prevent or reverse these changes. Results will inform therapies to reduce disability, mortality, and healthcare expenses.
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