Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium (Cai2+) concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of Cai2+ levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

Disrupted Calcium Homeostasis in Duchenne Muscular Dystrophy: A Common Mechanism behind Diverse Consequences

“…Among drugs which directly influence Ca 2+ homeostasis those causing inhibition of Ca 2+ channels in the sarcoplasmic membrane, stabilization of ryanodine receptors in SR/ER, overexpression of SERCA and reduction of the opening probability of MPTP were found to be of significance [124,125]. In a recent study, treatment of mdx mice with SERCA activator reduced cytosolic Ca 2+ levels, restored mitochondrial function, enhanced muscular strength, reduced muscular degeneration and fibrosis.…”

A revised model for mitochondrial dysfunction in Duchenne muscular dystrophy

“…35 Accordingly, the excessive entry of Ca 2+ into the damaged myofiber initiates mitochondrial structural with subsequent functional defects reducing ATP production, and promoting a downstream cascade, leading to myofiber degeneration. Forty-five years later, through the discovery in the late eighties of the dystrophin gene and its role in DMD, the basic dogma of mitochondrial dysfunction has not much evolved, [36][37][38] assuming still that the mitochondria of the dystrophic muscle are merely passively exposed to the external insult of Ca +2 overload. Based on, 32 we are suggesting now a modified model for the explanation of mitochondrial dysfunction in DMD, which is presented in figure 1.…”

Orai1–STIM1 Regulates Increased Ca2+ Mobilization, Leading to Contractile Duchenne Muscular Dystrophy Phenotypes in Patient-Derived Induced Pluripotent Stem Cells

“…Ca 2+ overload is a dystrophic phenotype that contributes to DMD pathogenesis [ 18 ]. While it has been proposed that Ca 2+ overload triggers initial molecular pathogenesis, in turn leading to functional phenotypes, such as contractile dysfunction or muscle fiber degeneration, whether Ca 2+ overload genuinely causes pathological changes in humans remains elusive.…”

“…Using commercially available Ca 2+ inhibitors/modulators, we identified that SOCs were the most attractive targets for regulating dystrophin deficiency-mediated Ca 2+ overload. The role of SOCs in abnormal Ca 2+ handling in DMD has been investigated, and targeting of SOCs to restore Ca 2+ homeostasis for DMD therapies has been discussed previously [ 18 , 54 ]. While Orai1 and STIM1 are major components of SOCs, other Ca 2+ channels, such as TRPC1, TRPV, and TRPM7, also contribute to SOC activity [ 55 , 56 ].…”

“…Ca 2+ overload has been widely accepted as a candidate regulating DMD pathogenesis [ 18 ]. However, whether modulating Ca 2+ overload has therapeutic effects for DMD in clinical settings remains largely unknown, due to the limited number of compounds available for clinical use or under development.…”