Remodeling of ryanodine receptor complex causes "leaky" channels: A molecular mechanism for decreased exercise capacity
Published online on February 11, 2008, 10.1073/pnas.0711074105 OPEN ACCESS ARTICLE
pnas.org
Could also have possibilities as performance enhancing drugs<g>
Andrew M. Bellinger*,{dagger}, Steven Reiken*,{dagger}, Miroslav Dura*,{dagger}, Peter W. Murphy*,{dagger}, Shi-Xian Deng{ddagger}, Donald W. Landry{ddagger}, David Nieman§, Stephan E. Lehnart*,{dagger}, Mahendranauth Samaru*,{dagger}, Alain LaCampagne¶, and Andrew R. Marks*,{dagger},{ddagger},||
*Clyde and Helen Wu Center for Molecular Cardiology, Departments of {dagger}Physiology and Cellular Biophysics and {ddagger}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
Contributed by Andrew R. Marks, November 21, 2007 (sent 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.
muscle fatigue | calcium channel | calstabin | exitation–contraction coupling | rycals
Footnotes
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.
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.
||To whom correspondence should be addressed. E-mail: arm42@columbia.edu |
