Absence of extraocular muscle pathology in Duchenne's muscular dystrophy: role for calcium homeostasis in extraocular muscle sparing.

Abstract

SummaryDuchenne muscular dystrophy (DMD) is characterized by clinical weakness and progressive necrosis of striated muscle as a consequence of dystrophin deficiency. While all skeletal muscle groups are thought to be affected, enigmatically, the extraocular muscles (EOM) appear clinically unaffected. Here we show that dystrophin deficiency does not result in myonecrosis or pathologically elevated levels of intracellular calcium ([Ca2+]i) in EOM. At variance with a previous report, we find no evidence for dystrophin-related protein/utrophin up-regulation in EOM. In vitro experiments demonstrate that extraocular muscles are inherently more resistant to necrosis caused by pharmacologically elevated [Ca2+]i levels when compared with pectoral musculature. We believe that EOM are spared in DMD because of their intrinsic ability to maintain calcium homeostasis better than other striated muscle groups. Our results indicate that modulating levels of [Ca2+]i in muscle may be of potential therapeutic use in DMD.

Proteomic profiling of naturally protected extraocular muscles from the dystrophin-deficient mdx mouse

“…Low levels of CSQ seem to exacerbate abnormal cytosolic Ca 2+ -handling by impairing luminal Ca 2+ -buffering in the dystrophic sarcoplasmic reticulum. These pathological alterations appear not to be present in mdx EOM tissue [31], which agrees with the previously reported resistance of dystrophic EOM fibers to Ca 2+ -induced muscle degeneration [15]. The drastic increase in molecular chaperones suggests that mdx EOM is capable of sustained cellular stress responses, involving both low-and high-molecular-mass Hsp elements.…”

“…For example, intrinsic laryngeal and certain distal muscle fibers, as well as extraocular muscle (EOM), are protected from a severely degenerative phenotype in dystrophic organisms [5][6][7][8][9][10][11]. Although the contractile efficiency of EOM is weakened in various muscle-related pathologies, such as myasthenia gravis, myasthenic syndromes, botulism, and myotonia congenita [12][13][14], they are usually spared in DMD patients [15][16][17].…”

Postnatal suppression of myomesin, muscle creatine kinase and the M-line in rat extraocular muscle

“…The absence of the M-line system is consistent with known cytoskeletal organization differences between extraocular and other skeletal musculature (Cheng and Porter, 2002;Porter et al, 2001a) and suggests that eye muscle may use novel mechanisms to transmit contractile force to the sarcolemma and tendon. We speculate that such differences in the myofilament-cytoskeleton-sarcolemma-extracellular matrix linkage may underlie the established protection of EOM in dystrophin-glycoprotein complex-based muscular dystrophies (Kaminski et al, 1992;Karpati and Carpenter, 1986;Khurana et al, 1995;Porter and Karathanasis, 1998;Porter et al, , 2001bRagusa et al, 1996).…”

Distinctive morphological and gene/protein expression signatures during myogenesis in novel cell lines from extraocular and hindlimb muscle

“…EOM expression profiles during development and in the adult are highly divergent from those of hindlimb (17,18,29,66). Such novel baseline properties of EOM may, in turn, precondition its sparing in the dystrophin-glycoprotein complex-based muscular dystrophies (40,42,43,45,61,65,69,(72)(73)(74)94) and heightened sensitivity to disorders such as myasthenia gravis (41,66). Because neuromuscular diseases are often not fully penetrant, and targeted muscle groups can vary, it may be impossible to understand disease mechanisms without an in-depth knowledge of muscle allotypes.…”