The calcineurin signal transduction pathway is essential for successful muscle regeneration in mdx dystrophic mice

Although mdx mice share the same genetic defect and lack dystrophin expression as in Duchenne muscular dystrophy (DMD), their limb muscles have a high regenerative capacity that ensures a more benign phenotype and essentially normal function. The cellular pathways responsible for this enhanced regenerative capacity are unknown. We tested the hypothesis that the calcineurin signal transduction pathway is essential for the successful regeneration following severe degeneration observed in the limb muscles of young mdx mice (2–4 weeks old) and that inhibition of this pathway using cyclosporine A (CsA) would exacerbate the dystrophic pathology. Eighteen-day-old mdx and C57BL/10 mice were treated with CsA for 16 days. CsA administration severely disrupted muscle regeneration in mdx mice, but had minimal effect in C57BL/10 mice. Muscles from CsA-treated mdx mice had fewer centrally nucleated fibers and extensive collagen, connective tissue, and mononuclear cell infiltration than muscles from vehicle-treated littermates. The deleterious effects of CsA on muscle morphology were accompanied by a 30–35% decrease in maximal force producing capacity. Taken together, these observations indicate that the calcineurin signal transduction pathway is a significant determinant of successful skeletal muscle regeneration in young mdx mice. Up-regulating this pathway may have clinical significance for DMD.

Effect of training on activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase pathways in rat soleus muscle

1. The effect of a chronic programme of either low- or moderate-to-high-intensity treadmill running on the activation of the extracellular-signal regulated protein kinase (ERK1/2) and the p38 mitogen-activated protein kinase (MAPK) pathways was determined in rat muscle. 2. Sprague-Dawley rats were assigned to one of three groups: (i) sedentary (NT; n = 8); (ii) low-intensity training (8 m/min; LIT; n = 16); and (iii) moderate-to-high-intensity training (28 m/min; HIT;n = 16). The training regimens were planned so that animals covered the same distance and had similar glycogen utilization for both LIT and HIT exercise sessions. 3. A single bout of LIT or HIT following 8 weeks of training led to a twofold increase in the phosphorylation of ERK1/2 (P = 0.048) and a two- to threefold increase in p38 MAPK (P = 0.005). Extracellular signal-regulated kinase 1/2 phosphorylation in muscle sampled 48 h after the last exercise bout was similar to sedentary values, while p38 MAPK phosphorylation was 70-80% lower than sedentary. One bout of LIT or HIT increased total ERK1/2 and p38 MAPK expression, with the magnitude of this increase being independent of prior exercise intensity or duration. Extracellular signal-regulated kinase 1/2 expression was increased three- to fourfold in muscle sampled 48 h after the last exercise bout irrespective of the prior training programme (P = 0.027), but p38 MAPK expression was approximately 90% lower than sedentary values. 4. In conclusion, exercise-training of different intensities/durations results in selective postexercise activation of intracellular signalling pathways, which may be one mechanism regulating specific adaptations induced by diverse training programmes.