Increased CaVbeta1A expression with aging contributes to skeletal muscle weakness.
Ca2+ 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 Ca2+ 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 alpha1s (CaV1.1) and beta1a (CaVbeta1a) subunits, both of which are necessary for E-C coupling to occur. While previous studies have found CaV1.1 expression declines in old rodents, CaVbeta1a expression has not been previously examined in aging models. Western blot analysis shows a substantial increase of CaVbeta1a expression over the full lifespan of Friend Virus B (FVB) mice. To examine the specific effects of CaVbeta1a overexpression, a CaVbeta1a-YFP plasmid was electroporated in vivo into young animals. The resulting increase in expression of CaVbeta1a corresponded to decline of CaV1.1 over the same time period. YFP fluorescence, used as a measure of CaVbeta1a-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 CaVbeta1a-YFP electroporated muscle fibers compared with sham-electroporated, age-matched controls. siRNA interference of CaVbeta1a in young muscles reduced charge movement, while charge movement in old was restored to young control levels. These studies imply CaVbeta1a serves as both a positive and negative regulator CaV1.1 expression, and that endogenous overexpression of CaVbeta1a during old age may play a role in the loss of specific force.
Taylor
Jackson R
JR
Department of Internal Medicine-Gerontology, Wake Forest University School of Medicine, 1 Medical Center Boulvard, Winston Salem, NC 27157, USA.
Zheng
Zhenlin
Z
Wang
Zhong-Min
ZM
Payne
Anthony M
AM
Messi
María L
ML
Delbono
Osvaldo
O
D000199:Actins / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D003600:Cytosol / Q000502:physiology; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D006614:Hindlimb; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018908:Muscle Weakness / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000502:physiology* / Q000503:physiopathology; D021122:Protein Subunits / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000502:physiology
D000199:Actins; C492923:Cacnb1 protein, mouse; D020746:Calcium Channels, L-Type; D021122:Protein Subunits; D002118:Calcium