Nerve-evoked contractile activity in skeletal muscle regulates transcript and protein levels of many metabolic genes in a coordinate fashion, including the muscle isozyme of glycogen phosphorylase (MGP). Cellular signaling mechanisms mediating the activity-dependent modulation of MGP transcript levels were investigated in a spontaneously contractile rat skeletal muscle cell line (Rmo). Mechanisms regulating MGP mRNA levels in Rmo myotubes were compared with those previously shown to modulate the gene encoding the α subunit of the acetylcholine receptor (αAChR). Reducing the resting membrane potential from -78 to -30 mV, either electrochemically (KCI) or by increasing Na+ permeability (veratridine): (1) prevented activation of transverse tubules, (2) impeded calcium release by the sarcoplasmic reticulum (SR), and (3) blocked Rmo contractility. MGP mRNA levels decreased to 30% of control levels and αAChR levels increased to 350% following 24 h of depolarization. Differing mechanisms appear to mediate this voltage-dependent regulation of MGP and αAChR. Inhibition of SR calcium efflux selectively decreased MGP mRNA levels by 30-50% when using dantrolene, thapsigargin, or a dose of ryanodine shown to inactivate Ca2+-induced SR Ca2+ release (CICR). By contrast, blockade of voltage sensors in transverse tubules with nifedipine, a dihydroaminopyridine (DHAP) antagonist, selectively increased αAChR mRNA levels by twofold. These data indicate that the voltage-dependent regulation of AChR gene expression differs from that modulating the MGP gene. KCl-induced depolarization and dantrolene both inhibit pulsatile SR Ca2+ efflux in Rmo myotubes, but by differing mechanisms. Depolarization and dantrolene comparably reduced MGP mRNA levels and decreased MGP transcript stability from a t( 1/2 ) of 24 h to 14.5 and 16 h, respectively. Reduced transcript stability can account for the observed reduction in mRNA levels of MGP in noncontractile Rmo myotubes and could be a significant regulatory mechanism in skeletal muscle that coordinates the activity-dependent expression of MGP with other glycogenolytic genes. (C) 2000 Wiley-Liss, Inc.
|Original language||English (US)|
|Number of pages||16|
|Journal||Journal of Cellular Physiology|
|State||Published - 2000|
ASJC Scopus subject areas
- Clinical Biochemistry
- Cell Biology