Overactivity of exercise-sensitive cation channels and their impaired modulation by IGF-1 in mdx native muscle fibers: Beneficial effect of pentoxifylline

• Main Authors: Jean-François Rolland, Annamaria De Luca, Rosa Burdi, Francesca Andreetta, Paolo Confalonieri, Diana Conte Camerino
• Format: Article
• Language: English
• Published: Elsevier 2006-12-01
• Series: Neurobiology of Disease
• Subjects: In vivo exercise; Muscular dystrophy; mdx mouse; Patch-clamp recordings; Voltage-insensitive cation channels; IGF-1 and cAMP modulation
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996106001987

Cell-attached patch-clamp recordings on native striated myofibers from adult dystrophic mdx mice revealed a higher occurrence and open probability compared to non-dystrophic wild-type myofibers of a 30 pS voltage-insensitive Ca2+-permeable channel, inhibited by Gd3+, streptomycin and ruthenium red. Myofibers from in vivo exercised animals had higher channel occurrence and/or open probability. Insulin-like growth factor 1 (3.3 nM) induced and/or enhanced channel activity, via PI3 kinase, in wild-type but not in mdx myofibers. Interestingly, in both genotypes the current was silenced by db-cAMP or pentoxifylline, a phosphodiesterase inhibitor. The channel activity/occurrence in pentoxifylline-treated exercised mdx (50 mg/kg/day i.p. for 4–8 weeks) overlapped that of exercised wild-type mice. Thus, a growth factor-sensitive current, likely due to a TRP channel, is activated in vivo by exercise in native striated fibers; its deregulation in the absence of dystrophin may contribute to Ca2+ homeostasis alteration. The possibility to pharmacologically counteract abnormal channel activity discloses important therapeutic application.