title: Remodeling of ryanodine receptor complex causes "leaky" channels: a molecular mechanism for decreased exercise capacity.
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.
authors.affiliation: Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Bellinger
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dura
authors.forename: Peter W
authors.initials: PW
authors.lastname: Murphy
authors.forename: Shi-Xian
authors.initials: SX
authors.lastname: Deng
authors.forename: Donald W
authors.initials: DW
authors.lastname: Landry
authors.forename: David
authors.initials: D
authors.lastname: Nieman
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Lehnart
authors.forename: Mahendranauth
authors.initials: M
authors.lastname: Samaru
authors.forename: Alain
authors.initials: A
authors.lastname: LaCampagne
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D015444:Exercise; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel