Abstract
The Stac3 gene is exclusively expressed in skeletal muscle, and Stac3 knockout is perinatal lethal in mice. Previous data from Stac3-deleted diaphragms indicated that Stac3-deleted skeletal muscle could not contract because of defective excitation-contraction (EC) coupling. In this study, we determined the contractility of Stac3-deleted hindlimb muscle. In response to frequent electrostimulation, Stac3-deleted hindlimb muscle contracted but the maximal tension generated was only 20% of that in control (wild type or heterozygous) muscle (P < 0.05). In response to high [K+], caffeine, and 4-chloro-m-cresol (4-CMC), the maximal tensions generated in Stac3-deleted muscle were 29% (P < 0.05), 58% (P = 0.08), and 55% (P < 0.05) of those in control muscle, respectively. In response to 4-CMC or caffeine, over 90% of myotubes formed from control myoblasts contracted, but only 60% of myotubes formed from Stac3-deleted myoblasts contracted (P = 0.05). However, in response to 4-CMC or caffeine, similar increases in intracellular calcium concentration were observed in Stac3-deleted and control myotubes. Gene expression and histological analyses revealed that Stac3-deleted hindlimb muscle contained more slow type-like fibers than control muscle. These data together confirm a critical role of STAC3 in EC coupling but also suggest that STAC3 may have additional functions in skeletal muscle, at least in the hindlimb muscle.
Highlights
The diaphragm muscle from Stac[3] knockout mice did not contract in response to electric stimulation but generated normal tension when stimulated by the RyR agonist 4-CMC11
When stimulated by single electric pulses, E18.5 Stac3−/− hindlimb muscles did not contract whereas E18.5 Stac3+/− hindlimb muscles generated twitches (Fig. 1A)
One second after the stimulation was stopped, Stac3+/− muscles completely relaxed but Stac3−/− muscles remained in contraction (Fig. 1A)
Summary
The diaphragm muscle from Stac[3] knockout mice did not contract in response to electric stimulation but generated normal tension when stimulated by the RyR agonist 4-CMC11. The gene encoding the major fast MHC protein Myh[4] is not expressed in the diaphragm, but it is abundantly expressed in the hindlimb muscles[25]. These and other differences between the diaphragm and hindlimb muscles prompted us to examine the effect of Stac[3] knockout on the contractility of hindlimb skeletal muscles in mice. Our data indicate that while EC coupling is impaired, it is not the sole cause for the markedly reduced contractility in Stac3-deleted hindlimb muscles
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