Remodeling of ryanodine receptor complex causes "leaky" channels: a molecular mechanism for decreased exercise capacity.
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.
Bellinger
Andrew M
AM
Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Reiken
Steven
S
Dura
Miroslav
M
Murphy
Peter W
PW
Deng
Shi-Xian
SX
Landry
Donald W
DW
Nieman
David
D
Lehnart
Stephan E
SE
Samaru
Mahendranauth
M
LaCampagne
Alain
A
Marks
Andrew R
AR
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*
D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel