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Inhibition of mechanosensitive cation channels inhibits myogenic differentiation by suppressing the expression of myogenic regulatory factors and caspase-3 activity

Nia Wedhas^*, Henry J. Klamut^*,, Charu Dogra^*, Apurva K. Srivastava^*,, Subburaman Mohan^*,, and Ashok Kumar^*,,1

^* Molecular Genetics Division, Musculoskeletal Disease Center, Jerry L. Pettis VA Medical Center, Loma Linda, California, USA;
Department of Medicine, and
Department of Biochemistry, Loma Linda University, Loma Linda, California, USA

¹Correspondence: Molecular Genetics Division, Musculoskeletal Disease Center, Jerry L. Pettis VA Medical Center, 11201 Benton St. (151), Loma Linda, CA 92354, USA. E-mail: Ashok.Kumar2{at}med.va.gov

Mechanosensitive cation channels (MSC) are ubiquitous in eukaryotic cell types. However, the physiological functions of MSC in several tissues remain in question. In this study we have investigated the role of MSC in skeletal myogenesis. Treatment of C2C12 myoblasts with gadolinium ions (MSC blocker) inhibited myotube formation and the myogenic index in differentiation medium (DM). The enzymatic activity of creatine kinase (CK) and the expression of myosin heavy chain-fast twitch (MyHCf) in C2C12 cultures were also blocked in response to gadolinium. Treatment of C2C12 myoblasts with gadolinium ions did not affect the expression of either cyclin A or cyclin D1 in DM. Other inhibitors of MSC such as streptomycin and GsTMx-4 also suppressed the expression of CK and MyHCf in C2C12 cultures. The inhibitory effect of gadolinium ions on myogenic differentiation was reversible and independent of myogenic cell type. Real-time-polymerase chain reaction analysis revealed that inhibition of MSC decreases the expression of myogenic transcription factors MyoD, myogenin, and Myf-5. Furthermore, the activity of skeletal -actin promoter was suppressed on MSC blockade. Treatment of C2C12 myoblasts with gadolinium ions prevented differentiation-associated cell death and inhibited the cleavage of poly (ADP-ribose) polymerase and activation of caspase-3. On the other hand, delivery of active caspase-3 protein to C2C12 myoblasts reversed the inhibitory effect of gadolinium ions on myogenesis. Our data suggest that inhibition of MSC suppresses myogenic differentiation by inhibiting the caspase-3 activity and the expression of myogenic regulatory factors.—Wedhas, N., Klamut, H. J., Dogra, C., Srivastava, A. K., Mohan, S., Kumar, A. Inhibition of mechanosensitive cation channels inhibits myogenic differentiation by suppressing the expression of myogenic regulatory factors and caspase-3 activity.

Key Words: mechanosensitive cation channels • gadolinium • myogenesis • C2C12 • caspase-3 • apoptosis.

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