Stimulation of calcineurin Aα activity attenuates muscle pathophysiology inmdxdystrophic mice

Abstract

Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin Aalpha transgene (CnAalpha) was overexpressed in skeletal muscles of mdx (mdx CnAalpha*) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnAalpha* and mdx mice was examined in vitro. Hindlimb muscles from mdx CnAalpha* mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnAalpha* than mdx mice. In the diaphragm, despite a slower phenotype and a approximately 35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnAalpha* compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity.

NRIP is a novel Z-disc protein to activate calmodulin signaling for skeletal muscle contraction and regeneration

“…Consistently, activation of the expression of oxidative fatigue-resistance slow-type fibers through CaN-NFAT signaling is well documented (Harridge, 2007;Meissner et al, 2007). For example, the activation of CaN enhances muscle resistance to fatigue in mdx mice (a model of Duchenne muscular dystrophy) (Frey et al, 2008;Stupka et al, 2008) and increases the number of slow-twitch muscle fibers (Naya et al, 2000). By contrast, genetic disruption of CaN leads to a significant decrease in slow-twitch and oxidative fibers (Parsons et al, 2003).…”

Chronic AMPK stimulation attenuates adaptive signaling in dystrophic skeletal muscle

“…Indeed, it has been known for ϳ20 yr that slow, oxidative myofibers in both Duchenne muscular dystrophy (DMD) patients and the dystrophin-negative mdx mouse model of muscular dystrophy show significantly reduced damage compared with faster, more glycolytic muscle fibers (47,72). Based on our work (2,13,14,25,40,45) and that of others (26,63), the overarching hypothesis in our laboratory has been that evocation of the slow, oxidative skeletal muscle phenotype attenuates the dystrophic pathology and represents a physiologically relevant therapeutic possibility.…”

“…Indeed, it has been known for ϳ20 yr that slow, oxidative myofibers in both Duchenne muscular dystrophy (DMD) patients and the dystrophin-negative mdx mouse model of muscular dystrophy show significantly reduced damage compared with faster, more glycolytic muscle fibers (47,72). Based on our work (2,13,14,25,40,45) and that of others (26, 63), the overarching hypothesis in our laboratory has been that evocation of the slow, oxidative skeletal muscle phenotype attenuates the dystrophic pathology and represents a physiologically relevant therapeutic possibility.In dystrophic skeletal muscle, a small but growing number of intracellular signaling molecules are known to elicit the slow, oxidative myogenic program, such as calcineurin, NFAT,13,14,26,63), whereas the role of other phenotype-shifting proteins, including p38, SIRT1, and RIP 140, remains largely undefined. We have recently demonstrated that stimulation of PPAR␦ and AMPK signaling using the synthetic agonists GW501516 and 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), respectively, was able to evoke the slow myogenic program and rescue muscle function in mdx animals (40, 45).…”

Clinical Use of Immunosuppressants in Duchenne Muscular Dystrophy

“…Stupka et al 15,16 tested the hypothesis that the calcineurin signal transduction pathway is essential for the successful regeneration after severe degeneration (observed in the limb muscles of young mdx mice aged 2-4 weeks) and that inhibition of this pathway using CsA would exacerbate the dystrophic pathology. The authors treated 18-day-old mdx mice and C57BL/10 mice with CsA for 16 days.…”