Nonmechanical Roles of Dystrophin and Associated Proteins in Exercise, Neuromuscular Junctions, and Brains

Abstract

Dystrophin-glycoprotein complex (DGC) is an important structural unit in skeletal muscle that connects the cytoskeleton (f-actin) of a muscle fiber to the extracellular matrix (ECM). Several muscular dystrophies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, congenital muscular dystrophies (dystroglycanopathies), and limb-girdle muscular dystrophies (sarcoglycanopathies), are caused by mutations in the different DGC components. Although many early studies indicated DGC plays a crucial mechanical role in maintaining the structural integrity of skeletal muscle, recent studies identified novel roles of DGC. Beyond a mechanical role, these DGC members play important signaling roles and act as a scaffold for various signaling pathways. For example, neuronal nitric oxide synthase (nNOS), which is localized at the muscle membrane by DGC members (dystrophin and syntrophins), plays an important role in the regulation of the blood flow during exercise. DGC also plays important roles at the neuromuscular junction (NMJ) and in the brain. In this review, we will focus on recently identified roles of DGC particularly in exercise and the brain.

Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress‐dependent, early event driving disuse atrophy

“…Increased sarcoplasmic nNOS amount in the presence of intact or repaired sarcolemma, as suggested by evidence concerning α1-syntrophin KO mice or micro-dystrophin transgenic mdx mice [14,45], or firmly anchored nNOS to a defective sarcolemma [46] does not cause nitrosative stress and muscle degeneration. Indeed, the amount and spatiotemporal distribution of NO apparently regulate muscle plasticity insofar as transient activation of sarcolemmal nNOS positively regulates myofiber perfusion and size [2,47,48], whereas sustained sarcoplasmic activation promotes atrophy [9][10][11]. Our present results indicate increased superoxide anion released by mitochondria as the source responsible for active nNOS redistribution after 6 h unloading.…”

Impaired regenerative capacity and lower revertant fibre expansion in dystrophin-deficient mdx muscles on DBA/2 background

“…DMD is caused by frameshift mutations leading to premature stop codons in the dystrophin (DMD ) gene, which precludes the synthesis of a protein called dystrophin23. Dystrophin, a large (427 kDa) actin-binding protein forms the dystrophin-glycoprotein complex (DGC) at the sarcolemma, in conjunction with dystrophin-associated proteins, such as dystroglycans, neuronal nitric oxide synthase, and sarcoglycans, to name a few45. Dystrophin deficiency perturbs the assembly of DGC and destabilizes the muscle membrane, making it more vulnerable to injury when exposed to stress during muscle contraction or stretch.…”

Eteplirsen in the treatment of Duchenne muscular dystrophy

“…DMD is caused by mutations in the DMD gene coding for dystrophin,1,6 a membrane-associated protein that links cytoskeletal actin in muscle fibers with the surrounding extracellular matrix by forming a network with sarcolemmal glycoproteins (otherwise known as the dystrophin-associated glycoprotein complex [DAGC]) 7–9. This linkage strengthens muscle structure during stressful contraction/relaxation cycles;10 recent studies, however, indicate that dystrophin also has nonmechanical roles 11. Dystrophin has four domains: an N-terminal domain for binding actin, a rod domain mainly for structural flexibility, a cysteine-rich domain for facilitating protein–protein interactions, and a C-terminal domain for binding DAGC proteins at the sarcolemma 9,12.…”