| First Author | Bellinger AM | Year | 2008 |
| Journal | Proc Natl Acad Sci U S A | Volume | 105 |
| Issue | 6 | Pages | 2198-202 |
| PubMed ID | 18268335 | Mgi Jnum | J:132211 |
| Mgi Id | MGI:3775502 | Doi | 10.1073/pnas.0711074105 |
| Citation | Bellinger AM, et al. (2008) Remodeling of ryanodine receptor complex causes 'leaky' channels: a molecular mechanism for decreased exercise capacity. Proc Natl Acad Sci U S A 105(6):2198-202 |
| abstractText | 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. |
