Remodeling of ryanodine receptor complex causes “leaky” channels: A molecular mechanism for decreased exercise capacity
- Andrew M. Bellinger*,†,
- Steven Reiken*,†,
- Miroslav Dura*,†,
- Peter W. Murphy*,†,
- Shi-Xian Deng‡,
- Donald W. Landry‡,
- David Nieman§,
- Stephan E. Lehnart*,†,
- Mahendranauth Samaru*,†,
- Alain LaCampagne¶, and
- Andrew R. Marks*,†,‡,‖
- *Clyde and Helen Wu Center for Molecular Cardiology,
- Departments of †Physiology and Cellular Biophysics and
- ‡Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032;
- §Department of Health, Leisure, and Exercise Science, Appalachian State University, Boone, NC 28608; and
- ¶Institut National de la Santé et de la Recherche Médicale, U 637, Unité de Formation et de Recherche de Médecine, Université Montpellier 1, F-34925 Montpellier, France
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Contributed by Andrew R. Marks, November 21, 2007 (received for review October 31, 2007)
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.
Footnotes
- ‖To whom correspondence should be addressed. E-mail: arm42{at}columbia.edu
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Author contributions: A.M.B., S.R., M.D., S.-X.D., D.W.L., D.N., S.E.L., A.L., and A.R.M. designed research; A.M.B., S.R., M.D., P.W.M., S.-X.D., D.N., S.E.L., M.S., and A.L. performed research; S.-X.D., D.L., and D.N. contributed new reagents/analytic tools; A.M.B., S.R., M.D., P.W.M., S.-X.D., D.W.L., D.N., S.E.L., M.S., A.L., and A.R.M. analyzed data; and A.M.B. and A.R.M. wrote the paper.
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Conflict of interest statement: A.R.M. and D.W.L. are on the scientific advisory board and own shares in ARMGO Pharma, Inc., a start-up company that is developing RyR targeted drugs for clinical use in the treatment of heart failure and sudden death. S.R. is a consultant for ARMGO Pharma, Inc.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0711074105/DC1.
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Freely available online through the PNAS open access option.
- © 2008 by The National Academy of Sciences of the USA
