Remodeling of ryanodine receptor complex causes "leaky" channels: a molecular mechanism for decreased exercise capacity
PainSci summary of Bellinger 2008?This page is one of thousands in the PainScience.com bibliography. It is not a general article: it is focused on a single scientific paper, and it may provide only just enough context for the summary to make sense. Links to other papers and more general information are provided at the bottom of the page, as often as possible. ★★★★☆?4-star ratings are for bigger/better studies and reviews published in more prestigious journals, with only quibbles. Ratings are a highly subjective opinion, and subject to revision at any time. If you think this paper has been incorrectly rated, please let me know.
“Exhausting exercise, such as that performed by a marathon runner or a long-distance cyclist, results in significant muscle damage and can impair task performance for days or weeks, although the mechanisms underlying this impairment in exercise capacity are not understood.” Lactic acid is usually blamed for “the burn” of intense exercise, but recent evidence strongly suggests that changes in the handling of calcium ions is more relevant to muscle fatigue. This (rather technical) basic physiology experiment showed that a major “calcium ion release channel” in cells walls becomes less functional as you exercise. In the authors words, exercise “results in leaky channels … that play a role in limiting exercise capacity.”
original abstract
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.
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One article on PainScience.com cites Bellinger 2008 as a source:
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