DHPR alpha1S subunit controls skeletal muscle mass and morphogenesis.
The alpha1S subunit has a dual function in skeletal muscle: it forms the L-type Ca(2+) channel in T-tubules and is the voltage sensor of excitation-contraction coupling at the level of triads. It has been proposed that L-type Ca(2+) channels might also be voltage-gated sensors linked to transcriptional activity controlling differentiation. By using the U7-exon skipping strategy, we have achieved long-lasting downregulation of alpha1S in adult skeletal muscle. Treated muscles underwent massive atrophy while still displaying significant amounts of alpha1S in the tubular system and being not paralysed. This atrophy implicated the autophagy pathway, which was triggered by neuronal nitric oxide synthase redistribution, activation of FoxO3A, upregulation of autophagy-related genes and autophagosome formation. Subcellular investigations showed that this atrophy was correlated with the disappearance of a minor fraction of alpha1S located throughout the sarcolemma. Our results reveal for the first time that this sarcolemmal fraction could have a role in a signalling pathway determining muscle anabolic or catabolic state and might act as a molecular sensor of muscle activity.
Piétri-Rouxel
France
F
UMR 7215, CNRS, UMR S 974 Inserm, Institut de Myologie, Université Pierre et Marie Curie, Paris, France. france.pietri-rouxel@upmc.fr
Gentil
Christel
C
Vassilopoulos
Stéphane
S
Baas
Dominique
D
Mouisel
Etienne
E
Ferry
Arnaud
A
Vignaud
Alban
A
Hourdé
Christophe
C
Marty
Isabelle
I
Schaeffer
Laurent
L
Voit
Thomas
T
Garcia
Luis
L
D000818:Animals; D001343:Autophagy / Q000235:genetics; D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics*; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000196:embryology* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D014018:Tissue Distribution / Q000235:genetics
C529218:CACNA1S protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D021122:Protein Subunits; D052248:Nitric Oxide Synthase Type I