Orai1-dependent calcium entry promotes skeletal muscle growth and limits fatigue.
Store-operated Ca²⁺ entry (SOCE) in skeletal muscle involves signalling between stromal-interacting molecule 1 (STIM1) in the sarcoplasmic reticulum (SR) and Ca²⁺ selective Orai1 channels in the sarcolemma. Here we generate transgenic mice with muscle-specific expression of dominant-negative Orai1 (dnOrai1) and demonstrate that Orai1-dependent SOCE promotes growth and limits fatigue in adult skeletal muscle. dnOrai1 mice lack SOCE specifically in muscle but are fertile and thrive well into adulthood. Although muscle ultrastructure, excitation-contraction (EC) coupling, fibre type, and expression of other Ca²⁺ regulatory proteins are unaltered, dnOrai1 mice exhibit reduced body weight, muscle mass and fibre cross-sectional area. Importantly, during intense repetitive activity, dnOrai1 mice display increased susceptibility to fatigue at the single fibre, excised muscle and whole-animal levels. We further show that STIM1 and Orai1 proteins co-localize within the triad junction but do not exist in a preassembled context. These results show that Orai1-dependent SOCE has an important physiological role in muscles of adult mice.
Department of Physiology and Pharmacology, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Lan
L
Wei-Lapierre
Ellie M
EM
Carrell
Simona
S
Boncompagni
Feliciano
F
Protasi
Robert T
RT
Dirksen
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020013:Calcium Signaling / Q000235:genetics; D005260:Female; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024510:Muscle Development / Q000235:genetics; D018763:Muscle Fatigue / Q000235:genetics; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D000071740:ORAI1 Protein; D000071737:Stromal Interaction Molecule 1
D015220:Calcium Channels; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium