An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse

Sci Transl Med. 2019 Nov 6;11(517):eaaw1131. doi: 10.1126/scitranslmed.aaw1131.


Deciphering the mechanisms that govern skeletal muscle plasticity is essential to understand its pathophysiological processes, including age-related sarcopenia. The voltage-gated calcium channel CaV1.1 has a central role in excitation-contraction coupling (ECC), raising the possibility that it may also initiate the adaptive response to changes during muscle activity. Here, we revealed the existence of a gene transcription switch of the CaV1.1 β subunit (CaVβ1) that is dependent on the innervation state of the muscle in mice. In a mouse model of sciatic denervation, we showed increased expression of an embryonic isoform of the subunit that we called CaVβ1E. CaVβ1E boosts downstream growth differentiation factor 5 (GDF5) signaling to counteract muscle loss after denervation in mice. We further reported that aged mouse muscle expressed lower quantity of CaVβ1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaVβ1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaVβ1E analogous and show a correlation between CaVβ1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaVβ1E or GDF5 might be effective in reducing muscle mass loss in aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / metabolism*
  • Animals
  • Atrophy
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Denervation
  • Embryo, Mammalian / metabolism*
  • Exons / genetics
  • Female
  • Gene Expression Regulation, Developmental
  • Growth Differentiation Factor 5 / metabolism*
  • Humans
  • Male
  • Mice
  • Muscles / anatomy & histology*
  • Muscles / innervation
  • Neuromuscular Junction / metabolism
  • Organ Size
  • Physical Conditioning, Animal
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Splicing / genetics
  • Signal Transduction*
  • Young Adult


  • CACNA1S protein, mouse
  • Calcium Channels, L-Type
  • Growth Differentiation Factor 5
  • Protein Isoforms