Current Application of Cyclosporine A to Investigate Skeletal Muscle Adaptation

Kunihiro      Sakuma; Akihiko      Yamaguchi

Abstract

The immunosuppressive oligonucleotide cyclosporine A (CsA) is extensively used in organ transplantation and autoimmune disorders. CsA as well as FK506 is a typical inhibitor of calcineurin, a serine/threonine phosphatase. Calcineurin is a potent regulator for fiber-type conversion, regeneration, and muscle hypertrophy of slow-twitch fibers. Many researchers including our group have used CsA delivered orally, intraperitoneally, or subcutaneously to modulate calcineurin activity. In this review, we have systematically and descriptively dealt with the role of CsA in regulating muscle adaptations in mature mammals. Pharmacological inhibition by CsA delays the muscle regenerating process. Some limitations are observed, because treatment with CsA in vivo blocks all of the calcineurin subtypes. A strategy for controlling the amount of calcineurin may be effective for the treatment of muscular disorders such as Duchenne muscular dystrophy (DMD), Ullrich congenital muscular dystrophy (UCMD), and limb-girdle muscular dystrophy (LGMD). Lowdose and short-term (2-6 weeks) CsA treatment would help to elucidate the functional role of calcineurin in skeletal muscle in vivo.

Keywords: Cyclosporine A, calcineurin, regeneration, hypertrophy, fiber type, muscular dystrophy, skeletal muscle, cyclophilin D, autoimmune disorders, calmodulin