Skeletal muscle differentiation is tightly regulated by membrane potential dynamics and voltage-dependent ion channel activity. Potassium (K+) and calcium (Ca2+) currents coop- erate to orchestrate the transition of myoblasts into fusion-competent myotubes, and al- terations in this process are associated with dystrophic phenotypes. Here, we investigated the electrophysiological remodeling accompanying C2C12 myogenesis and the modula- tory effects of the polyphenol resveratrol (RES) on calcium voltage-gated channel subunit alpha 1 S (CACNA1S, Cav1.1, L-type) currents. Whole-cell patch-clamp recordings were performed in proliferating and differentiating C2C12 cells to characterize the temporal expression of K+ currents and voltage-dependent Ca2+ channels (VDCCs). During differ- entiation, three electrophysiological subpopulations were identified according to K+ cur- rent profiles: SK4+/EAG−/Kir−, SK4−/EAG+/Kir−, and SK4−/EAG+/Kir+. This sequence paralleled a progressive membrane hyperpolarization from −20 mV to −70 mV, consistent with the physiological maturation of myogenic cells. In C2C12 myocytes, nimodipine- sensitive L-type currents were the only Ca2+ conductance observed. Their activation threshold (~−30 mV) and half-activation voltage (V/2 ≈ −12 mV) indicated the coexpression of embryonic and adult Cav1.1 isoforms. Exposure to RES (30 μM, 48 h) pro- duced a depolarizing shift in activation (ΔV/2 ≈ +9 mV) and a reduction in current ampli- tude across all voltages, consistent with a transition toward the adult splice variant of Cav1.1. These findings suggest that RES promotes electrophysiological maturation of skel- etal muscle cells by modulating calcium channel expression and gating behavior. Given its known ability to correct splicing abnormalities in CACNA1S and related genes, resvera- trol emerges as a promising pharmacological agent for restoring calcium homeostasis in neuromuscular disorders such as myotonic dystrophy type 1 (DM1).
Modulation of L-Type Calcium Currents by Resveratrol-Induced Myogenesis in C2C12 Cells / Biagini, Andrea; Sallicandro, Luana; Covarelli, Jasmine; Gentile, Rosaria; Mirarchi, Alessandra; Farinelli, Alessio; Reali, Gianmarco; Del Bianco, Diletta; Quellari, Paola Tiziana; Gliozheni, Elko; Malvasi, Antonio; Baldini, Giorgio Maria; Trojano, Giuseppe; Tubaro, Claudia; Bearzi, Claudia; Rizzi, Roberto; Arcuri, Cataldo; Prontera, Paolo; Tinelli, Andrea; Fioretti, Bernard. - In: CELLS. - ISSN 2073-4409. - 15:7(2026). [10.3390/cells15070650]
Modulation of L-Type Calcium Currents by Resveratrol-Induced Myogenesis in C2C12 Cells
Gentile, Rosaria;Rizzi, Roberto;Prontera, Paolo;
2026
Abstract
Skeletal muscle differentiation is tightly regulated by membrane potential dynamics and voltage-dependent ion channel activity. Potassium (K+) and calcium (Ca2+) currents coop- erate to orchestrate the transition of myoblasts into fusion-competent myotubes, and al- terations in this process are associated with dystrophic phenotypes. Here, we investigated the electrophysiological remodeling accompanying C2C12 myogenesis and the modula- tory effects of the polyphenol resveratrol (RES) on calcium voltage-gated channel subunit alpha 1 S (CACNA1S, Cav1.1, L-type) currents. Whole-cell patch-clamp recordings were performed in proliferating and differentiating C2C12 cells to characterize the temporal expression of K+ currents and voltage-dependent Ca2+ channels (VDCCs). During differ- entiation, three electrophysiological subpopulations were identified according to K+ cur- rent profiles: SK4+/EAG−/Kir−, SK4−/EAG+/Kir−, and SK4−/EAG+/Kir+. This sequence paralleled a progressive membrane hyperpolarization from −20 mV to −70 mV, consistent with the physiological maturation of myogenic cells. In C2C12 myocytes, nimodipine- sensitive L-type currents were the only Ca2+ conductance observed. Their activation threshold (~−30 mV) and half-activation voltage (V/2 ≈ −12 mV) indicated the coexpression of embryonic and adult Cav1.1 isoforms. Exposure to RES (30 μM, 48 h) pro- duced a depolarizing shift in activation (ΔV/2 ≈ +9 mV) and a reduction in current ampli- tude across all voltages, consistent with a transition toward the adult splice variant of Cav1.1. These findings suggest that RES promotes electrophysiological maturation of skel- etal muscle cells by modulating calcium channel expression and gating behavior. Given its known ability to correct splicing abnormalities in CACNA1S and related genes, resvera- trol emerges as a promising pharmacological agent for restoring calcium homeostasis in neuromuscular disorders such as myotonic dystrophy type 1 (DM1).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
