Characterization of ARC, apoptosis repressor interacting with CARD, in normal and dystrophin-deficient skeletal muscle

Abstract

Duchenne muscular dystrophy is an X-linked recessive disorder, primarily characterized by progressive muscle weakness and wasting. The disease results from the absence of dystrophin, however the precise molecular mechanisms leading to muscle pathology are poorly understood. Dystrophic muscles undergo increased oxidative stress and altered calcium homeostasis, which may contribute to myofiber loss by triggering both necrosis and apoptosis. Recent studies have identified ARC (apoptosis repressor with caspase recruitment domain) as an abundant protein in human muscle that can inhibit both hypoxia and caspase-8-induced apoptosis as well as protect cells from oxidative stress. To explore a potential role for ARC in protecting muscle fibers from dystrophic breakdown, we have cloned and characterized murine ARC and studied its expression in normal and dystrophic mouse muscle. ARC is expressed at high levels in striated muscle and displays fiber-type restricted expression patterns. ARC expression levels are normal in dystrophic mdx mice, although the intracellular localization pattern of ARC is slightly altered compared with normal muscles. Overexpression of ARC in transgenic mdx mice failed to alleviate the dystrophic pathology in skeletal muscles, suggesting that misregulation of the molecular pathways regulated by ARC does not significantly contribute to myofiber death.

Differential apoptosis-related protein expression, mitochondrial properties, proteolytic enzyme activity, and DNA fragmentation between skeletal muscles

“…Unlike most antiapoptotic proteins, which mediate their action on one of the main apoptotic signaling pathways, ARC is able to regulate both the death receptor and mitochondrial pathway (35,46). ARC also has a unique tissue distribution, being highly expressed in cardiac and skeletal muscle but absent or low in other tissues (1,35). These unique characteristics suggest that ARC is likely a key regulator of apoptotic signaling in skeletal muscle.…”

“…First, skeletal muscle fibers are generally considered to be long-lived, terminally differentiated cells (1,35,44). Cell culture studies indicate that in contrast to the high rate of apoptosis and cell turnover observed during stages leading to myogenic differentiation, terminally differentiated myotubes are more resistant to apoptosis (70).…”

“…ARC is an antiapoptotic protein capable of inhibiting apoptosis mediated by both the death receptor and mitochondrial pathway (35,46). Interestingly, ARC is highly expressed in long-lived cells, such as cardiac and skeletal myocytes (1,35). In addition, it has been demonstrated that ARC is undetectable in undifferentiated H9c2 cells, but levels rise upon differentiation (33).…”

Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy

“…Genetic and pharmacological treatments designed to inhibit apoptosis also produce a moderate (10-20%) increase of lifespan in a mouse model of familial amyotrophic lateral sclerosis (22)(23)(24). Furthermore, treatment with cyclosporin A inhibits mitochondria-mediated apoptosis and improves muscle histology in collagen VI-deficient mice (25). On the other hand, overexpression of an apoptosis-inhibiting protein in dystrophindeficient mdx mouse muscles does not appear to ameliorate pathology (26).…”

Mechanisms of exercise-induced muscle damage and fatigue: Intracellular calcium accumulation

“…Mechanical overload, produced by ECC contractions, induces muscle damage, which leads to myofiber necrosis accompanied with ultrastructural collapse, edema and inflammation of myofibers [37][38][39][40] . These inflammatory reactions achieve their peak responses within 3 days after ECC contractions, and, subsequently, muscle fiber converts to the process of regeneration in ~7 days 6,39,41,42) . After ECC contractions, inflammatory responses progress over the first 3 days following insult, and damaged cells undergo phagocytosis 43,44) .…”