Modulation by prednisolone of calcium handling in skeletal muscle cells

Abstract

1 Increased calcium (Ca2") influx has been incriminated as a potential pathological mechanism in the chronic skeletal muscle degeneration exhibited by Duchenne muscular dystrophy (DMD) patients. We have studied the influence of the glucocorticoid a-methylprednisolone (PDN), the only drug known to have a beneficial effect on the degenerative course of DMD, on Ca2" handling in the C2 skeletal muscle cell line. 2 PDN, when added 3 days (when myoblasts start to fuse into myotubes) after cell seeding, led to a 2 to 4 fold decrease in cellular Ca21 uptake. This decrease was independent of the extracellular Ca2+ concentration applied to cells. The effect took at least 24 h in order to become established (PDN of l0-5 M) and took longer for lower PDN concentrations (ECm of ca. 10-6 M at day 5, 10-6.5 M at day 7 and i0-7 5 M at day 9 in culture). 3 Cellular calcium accumulation was also decreased in PDN-treated myotubes exposed to 45Ca2+-containing medium for 1 to 6 days. 4 No effect of PDN was seen on 45Ca2+ efflux; a decrease in the amount of 45Ca2+released was observed due to the reduction of cellular 45Ca2+ loading.

Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A2-dependent mechanism

“…It should be noted that although the present and other studies (7,37,40,45) are consistent with SOCE in skeletal muscle cells, the influence of glucocorticoids on muscle calcium entry and concentrations has been examined only in a few previous studies, with apparently conflicting results (41,51,57,74). The present finding of increased calcium entry and concentrations in muscle cells treated with dexamethasone is consistent with a report by Vandebrouck et al (74).…”

“…The influence of glucocorticoids on muscle calcium homeostasis, however, is not well understood. Previous reports concerning the effects of glucocorticoids on calcium entry and concentrations in myocytes provided contradictory results, with evidence of both increased (74) and reduced (41,51,57) influx and cytosolic concentrations of calcium in glucocorticoid-treated muscle cells.…”

Evolving Therapeutic Strategies for Duchenne Muscular Dystrophy: Targeting Downstream Events

“…For example, prednisone can modulate proteolysis and calcium handling, enhance myogenesis, and inhibit apoptosis (71)(72)(73)(74)(75)(76). The ability of prednisone to have direct effects on muscle cells is further supported by findings using Caenorhabditis elegans, which lack an immune system.…”

Practice Parameter: Corticosteroid treatment of Duchenne dystrophy [RETIRED]

“…Investigators have proposed various possibilities based mainly on observations in mouse models of muscular dystrophy and on a limited number of studies in patients. 8 These possibilities include 1) altering the mRNA levels of structural, signaling, and immune response genes 9 ; 2) reducing cytotoxic T lymphocytes 10,11 ; 3) lowering calcium influx and concentration 12,13 ; 4) increasing laminin expression and myogenic repair 14 ; 5) retarding muscle apoptosis and cellular infiltration 15 ; 6) enhancing dystrophin expression 16 ; 7) affecting neuromuscular transmission 17 ; 8) protecting against mechanically induced fiber damage 18 ; 9) attenuating muscle fiber necrosis 19 ; 10) slowing the rate of skeletal muscle breakdown [20][21][22] ; and 11) increasing muscle levels of taurine and creatine. 23 More studies are necessary to establish the precise cellular mechanism(s) by which corticosteroids produce their beneficial effects in DD.…”