Remodeling of ryanodine receptor complex causes "leaky" channels: A molecular mechanism for decreased exercise capacity Academic Article uri icon


MeSH Major

  • Adaptation, Physiological
  • Calcium Channels
  • Exercise
  • Ryanodine Receptor Calcium Release Channel


  • During exercise, defects in calcium (Ca2+) release have been proposed to impair muscle function. Here, we show that during exercise in mice and humans, the major Ca2+ release channel required for excitation-contraction coupling (ECC) in skeletal muscle, the ryanodine receptor (RyR1), is progressively PKA-hyperphosphorylated, S-nitrosylated, and depleted of the phosphodiesterase PDE4D3 and the RyR1 stabilizing subunit calstabin1 (FKBP12), resulting in "leaky" channels that cause decreased exercise tolerance in mice. Mice with skeletal muscle-specific calstabin1 deletion or PDE4D deficiency exhibited significantly impaired exercise capacity. A small molecule (S107) that prevents depletion of calstabin1 from the RyR1 complex improved force generation and exercise capacity, reduced Ca2+-dependent neutral protease calpain activity and plasma creatine kinase levels. Taken together, these data suggest a possible mechanism by which Ca2+ leak via calstabin1-depleted RyR1 channels leads to defective Ca2+ signaling, muscle damage, and impaired exercise capacity.

publication date

  • February 12, 2008



  • Academic Article



  • eng

PubMed Central ID

  • PMC2538898

Digital Object Identifier (DOI)

  • 10.1073/pnas.0711074105

PubMed ID

  • 18268335

Additional Document Info

start page

  • 2198

end page

  • 202


  • 105


  • 6