Fibrosis is a pathological feature observed in patients with Duchenne muscular dystrophy (DMD) and in mdx mice, the experimental model of DMD. We evaluated the effect of suramin, a transforming growth factor-beta 1 (TGF-β1) blocker, on fibrosis in mdx mice. mdx mice (6 months old) received suramin for 7 weeks. Suramin- and saline-treated (control) mdx mice performed exercise on a treadmill to worsen disease progression. Immunoblotting showed an increase of TGF-β1 in mdx diaphragm, limb, and cardiac muscles. Suramin decreased creatine kinase in mdx mice and attenuated fibrosis in all muscles studied, except for cardiac muscle. Suramin protected limb muscles against damage and reduced the exercise-induced loss of strength over time. These findings support a role for TGF-β1 in fibrinogenesis and myonecrosis during the later stages of disease in mdx mice. Suramin might be a useful therapeutic alternative for the treatment of dystrophinopathies.

Matsumura CY, Taniguti AP, Pertille A, Santa Neto H, Marques MJ. Stretch-activated calcium channel protein TRPC1 is correlated with the different degrees of the dystrophic phenotype in mdx mice. Am J Physiol Cell Physiol 301: C1344 -C1350, 2011. First published September 7, 2011; doi:10.1152/ajpcell.00056.2011In Duchenne muscular dystrophy (DMD) and in the mdx mouse model of DMD, the lack of dystrophin is related to enhanced calcium influx and muscle degeneration. Stretch-activated channels (SACs) might be directly involved in the pathology of DMD, and transient receptor potential cation channels have been proposed as likely candidates of SACs. We investigated the levels of transient receptor potential canonical channel 1 (TRPC1) and the effects of streptomycin, a SAC blocker, in muscles showing different degrees of the dystrophic phenotype. Mdx mice (18 days old, n ϭ 16) received daily intraperitoneal injections of streptomycin (182 mg/kg body wt) for 18 days, followed by removal of the diaphragm, sternomastoid (STN), biceps brachii, and tibialis anterior muscles. Control mdx mice (n ϭ 37) were injected with saline. Western blot analysis showed higher levels of TRPC1 in diaphragm muscle compared with STN and limb muscles. Streptomycin reduced creatine kinase and prevented exercise-induced increases of total calcium and Evans blue dye uptake in diaphragm and in STN muscles. It is suggested that different levels of the stretch-activated calcium channel protein TRPC1 may contribute to the different degrees of the dystrophic phenotype seen in mdx mice. Early treatment designed to regulate the activity of these channels may ameliorate the progression of dystrophy in the most affected muscle, the diaphragm. dystrophinopaties; streptomycin; Duchenne muscular dystrophy; transient receptor potential canonical channel 1 IN DUCHENNE MUSCULAR DYSTROPHY (DMD) and in the mdx mouse model of DMD, the lack of dystrophin is associated with progressive myonecrosis of skeletal muscles that leads to respiratory failure, the main cause of death in this disease (5,8). Dystrophin is part of the dystrophin-glycoprotein complex, a multisubunit complex that plays a role in maintaining the integrity of the sarcolemma during the stress imposed by muscle contraction (9). Although the mechanisms responsible for myonecrosis are still not completely understood, the chronic increase of cytosolic Ca 2ϩ concentration seen in mdx mice and in DMD (22,29,34) is generally accepted to be closely related to the process of muscle damage, possibly by activating proteases implicated in muscle necrosis (41).Stretch-activated channels (SACs) respond to mechanical stress with increased open probability (19), are permeable to both Na ϩ and Ca 2ϩ (12, 13), and have been suggested to be primarily involved in the pathogenesis of DMD (14, 42, 44). The transient receptor potential (TRP) channels are a family of proteins that regulate calcium entry into cells, and recent findings have suggested that the canonical TRPC1 and TRPC6 channels are key players in muscle m...

In the mdx mouse model of Duchenne muscular dystrophy, the lack of dystrophin is associated with increased calcium levels and skeletal muscle myonecrosis. The intrinsic laryngeal muscles (ILM) are protected and do not undergo myonecrosis. We investigated whether this protection is related to an increased expression of calcium-binding proteins, which may protect against the elevated calcium levels seen in dystrophic fibers. The expression of sarcoplasmic-endoplasmic-reticulum Ca(2+)-ATPase and calsequestrin was examined in ILM and in nonspared limb muscles of control and mdx mice using immunofluorescence and immunoblotting. Dystrophic ILM presented a significant increase in the proteins studied when compared to controls. The increase of Ca(2+)-handling proteins in dystrophic ILM may permit better maintenance of calcium homeostasis, with the consequent absence of myonecrosis. The results further support the concept that abnormal Ca(2+)-handling is involved in dystrophinopathies. Muscle Nerve, 2009.

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The lack of dystrophin in mdx mice and in Duchenne muscular dystrophy causes sarcolemmal breakdown and increased calcium influx followed by myonecrosis. We examined whether the calcium channel blockers diltiazem and verapamil protect dystrophic muscles from degeneration. Mdx mice received daily intraperitoneal injections of diltiazem or verapamil for 18 days, followed by removal of the sternomastoid, diaphragm, tibialis anterior, and cardiac muscles. Control mdx mice were injected with saline. Both drugs significantly decreased blood creatine kinase levels. Total calcium content was significantly higher in mdx muscles than in control C57Bl/10. Verapamil and diltiazem reduced total calcium content only in diaphragm and cardiac muscle. Histological analysis showed that diltiazem significantly attenuated myonecrosis in diaphragm. Immunoblots showed a significant increase of calsequestrin and beta-dystroglycan levels in some diltiazem- and verapamil-treated muscles. Possible interactions of these drugs with the sarcoplasmic reticulum and sarcolemma may also contribute to the improvement of the dystrophic phenotype.