Abstract
SummaryLoss of strength in human and animal models of aging can be partially attributed to a well‐recognized decrease in muscle mass; however, starting at middle‐age, the normalized force (force/muscle cross‐sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation–contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full‐length TnT3 (FL‐TnT3) and its carboxyl‐terminal (CT‐TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA‐410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.
Highlights
Aging is associated with loss of muscle strength and power that contributes to fall risk, impaired mobility, and reduced quality of life (Alley et al, 2010)
To test whether troponin T3 (TnT3) regulates Cacna1s transcription, we knocked down TnT3 in mouse skeletal muscle in vivo to determine whether Cav1.1 expression depends on TnT3 regulation of Cacna1s
We compared flexor digitorum brevis (FDB) muscles 3 weeks after electroporation with control nontargeting or targeting TnT3 shRNA by immunoblot, and quantitative real-time PCR (Fig. 1A–C). shT’s efficiency in knocking down TnT3 was confirmed by immunoblot (Fig. 1A,B), which showed an over 70% (P < 0.05) decrease in endogenous TnT3 expression
Summary
Aging is associated with loss of muscle strength and power that contributes to fall risk, impaired mobility, and reduced quality of life (Alley et al, 2010). Cohort studies show that strength is lost two- to five-times faster than muscle mass with age (Goodpaster et al, 2006), and its loss is a more consistent risk factor for disability and death (Newman et al, 2006). The molecular mechanism responsible for the loss of muscle-contraction efficiency is decreased voltage-gated calcium channel a1 subunit (Cav1.1) (Renganathan et al, 1997). It is essential for muscle contraction and, with aging, uncouples more ryanodine receptors (RyR1s) through an undefined mechanism
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call