Dysregulation of calcium homeostasis in muscular dystrophies

Abstract

Muscular dystrophies are a group of diseases characterised by the primary wasting of skeletal muscle, which compromises patient mobility and in the most severe cases originate a complete paralysis and premature death. Existing evidence implicates calcium dysregulation as an underlying crucial event in the pathophysiology of several muscular dystrophies, such as dystrophinopathies, calpainopathies or myotonic dystrophy among others. Duchenne muscular dystrophy is the most frequent myopathy in childhood, and calpainopathy or LGMD2A is the most common form of limb-girdle muscular dystrophy, whereas myotonic dystrophy is the most frequent inherited muscle disease worldwide. In this review, we summarise recent advances in our understanding of calcium ion cycling through the sarcolemma, the sarcoplasmic reticulum and mitochondria, and its involvement in the pathogenesis of these dystrophies. We also discuss some of the clinical implications of recent findings regarding Ca2+ handling as well as novel approaches to treat muscular dystrophies targeting Ca2+ regulatory proteins.

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

“…Alternatively, calpain-3 appears to broadly support cellular Ca 2+ homeostasis by preventing degradation of SERCA proteins, supporting RyR1 function, and stabilizing the sarcomeric triad [17, 39, 51]. Of interest, loss-of-function mutations in calpain-3 are known to cause limb girdle muscular dystrophy type 2a (LGMD2a; also called calpainopathy) [27], and transgenic reduction of calpain-3 in mice causes severe Ca 2+ dysregulation [54]. At the mRNA level, expression of calpain-3 was ~50% lower in IBM samples vs. controls (q < 0.05).…”

MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload

“…Finally, there is increasing realization that mitochondrial calcium overload might be a final common pathway in a multitude of disease conditions including various myopathies, certain neurodegenerative diseases, models of heart failure, and ischemic tissue injury (Abeti and Abramov, 2015; Bhosale et al, 2015; Martin and McGee, 2014; Santulli et al, 2015; Vallejo-Illarramendi et al, 2014). As such, strategies that modulate mitochondrial calcium uptake might have wide therapeutic potential.…”

“…These entities are often accompanied by mitochondrial dysfunction and damage. Indeed, mitochondrial calcium overload is being increasingly viewed as a common final pathway for a wide range of human pathologies (Abeti and Abramov, 2015; Bhosale et al, 2015; Martin and McGee, 2014; Santulli et al, 2015; Vallejo-Illarramendi et al, 2014). Most of these conditions, like MICU1 deficiency, have few therapeutic options.…”

Concurrent Label-Free Mass Spectrometric Analysis of Dystrophin Isoform Dp427 and the Myofibrosis Marker Collagen in Crude Extracts from mdx-4cv Skeletal Muscles

“…Progressive diseases of skeletal and cardiac muscles with primary abnormalities in the dystrophin gene include Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy [10,11,12]. In X-linked muscular dystrophy, the almost complete absence of full-length dystrophin triggers a significant reduction in the dystrophin-associated glycoprotein complex and a plethora of down-stream pathophysiological changes, such as an altered coupling between neuronal excitation and muscle contraction, stretch-induced fiber injury, higher levels of plasmalemmal calcium influx, impaired luminal calcium buffering, and an accelerated proteolytic degradation rate [13,14,15]. In order to elucidate the enormous complexity and potential interconnectivity of these many secondary changes, damage pathways in dystrophic muscles involved in fiber degeneration, inflammation, fatty deposition, and progressive fibrosis are ideally studied by large-scale and comprehensive bioanalytical approaches, such as mass spectrometry-based proteomics [16].…”