Increased Ca V β 1a expression with aging contributes to skeletal muscle weakness

Summary Ca 2+ release from the sarcoplasmic reticulum (SR) into the cytosol is a crucial part of excitation–contraction (E‐C) coupling. Excitation–contraction uncoupling, a deficit in Ca 2+ release from the SR, is thought to be responsible for at least some of the loss in specific force observed in aging skeletal muscle. Excitation–contraction uncoupling may be caused by alterations in expression of the voltage‐dependent calcium channel α 1s (Ca V 1.1) and β 1a (Ca V β 1a ) subunits, both of which are necessary for E‐C coupling to occur. While previous studies have found Ca V 1.1 expression declines in old rodents, Ca V β 1a expression has not been previously examined in aging models. Western blot analysis shows a substantial increase of Ca V β 1a expression over the full lifespan of Friend Virus B (FVB) mice. To examine the specific effects of Ca V β 1a overexpression, a Ca V β 1a ‐YFP plasmid was electroporated in vivo into young animals. The resulting increase in expression of Ca V β 1a corresponded to decline of Ca V 1.1 over the same time period. YFP fluorescence, used as a measure of Ca V β 1a ‐YFP expression in individual fibers, also showed an inverse relationship with charge movement, measured using the whole‐cell patch‐clamp technique. Specific force was significantly reduced in young Ca V β 1a ‐YFP electroporated muscle fibers compared with sham‐electroporated, age‐matched controls. siRNA interference of Ca V β 1a in young muscles reduced charge movement, while charge movement in old was restored to young control levels. These studies imply Ca V β 1a serves as both a positive and negative regulator Ca V 1.1 expression, and that endogenous overexpression of Ca V β 1a during old age may play a role in the loss of specific force.