Abstract
During membrane depolarization associated with skeletal excitation-contraction (EC) coupling, L-type Ca2+ channels (dihydropyridine receptor (DHPR) in the transverse (t)-tubule membrane) undergo conformational changes that are transmitted to Ca2+-release channel (ryanodine receptor type 1) in the sarcoplasmic reticulum (SR) causing Ca2+ release from the SR. Canonical-type transient receptor potential cation channel 3 (TRPC3), an extracellular Ca2+ entry channel in the t-tubule and plasma membrane, is required for full-gain of skeletal EC coupling. The present study examined additional role(s) for TRPC3 in skeletal muscle other than mediation of EC coupling. We created a stable myoblast line (MDG/TRPC3 KD myoblast) with reduced TRPC3 expression by knock-down of TRPC3 using retrovirus-delivered small interference RNAs in α1SDHPR-null muscular dysgenic myoblasts to eliminate any DHPR-mediated EC coupling-related events. Unlike α1SDHPR-null muscular dysgenic myoblasts, MDG/TRPC3 KD myoblasts exhibited dramatic changes in cellular morphology (e.g., unusual expansion of both cell volume and the plasma membrane, and multi-nuclei) and increased Ca2+ content in both the endoplasmic reticulum and cytoplasm of resting myoblasts. Moreover, these myoblasts failed to differentiate into myotubes. Therefore, TRPC3 in skeletal myoblasts is essential for maintenance of skeletal muscle.
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