Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions

Weller, Boaz; Karpati, George; Carpenter, Stirling

doi:10.1016/0022-510x(90)90005-8

Cited by 210 publications

(153 citation statements)

References 24 publications

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“…The association of heightened contraction-induced injury with DGC-related muscular dystrophies was established more than 20 y ago (22,25,26). Based on these early reports, the DGC was proposed to directly limit susceptibility to contraction-induced injury, and this injury was proposed as a primary trigger of disease onset.…”

Section: Discussionmentioning

confidence: 99%

“…Muscles of mice deficient for dystrophin (mdx mice) display increased sarcolemmal damage, destabilization of sarcomeres, hypercontraction, and contraction-induced force deficits (22,(25)(26)(27). Muscles of mice that either lack DG or have mutations that render α-DG hypoglycosylated are significantly more susceptible to severe contraction-induced injury than those of WT counterparts (21).…”

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confidence: 99%

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Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contractioninduced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contractioninduced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions. muscular dystrophy | eccentric contraction | titin | skeletal muscle | dystroglycan

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Rader

Turk

Willer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…4,5 Therefore, after allowing a 10-min recovery period following the above measurements of isometric contractile properties, AdV-Dys-injected and control soleus muscles were also compared to determine their ability to withstand highstress eccentric (lengthening) contractions. The protocol has been described in detail previously.…”

Section: Measurement Of Isometric Contractile Propertiesmentioning

confidence: 99%

“…3 Dystrophin is a large cytoskeletal protein that is normally present on the cytoplasmic aspect of the myofiber surface membrane. 3 Current evidence suggests that myofibers lacking dystrophin are abnormally susceptible to contraction-induced sarcolemmal damage, 4,5 which secondarily leads to muscle fiber dysfunction, 6,7 necrosis and eventual replacement of the lost fibers by adipose and connective tissue. Therefore, the muscle weakness found in DMD patients is due to both myofiber loss and impaired contractile function in the surviving myofiber population.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

et al. 1998

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Duchenne muscular dystrophy (DMD) and murine X-linked logy and muscle weakness. The main findings are as folmuscular dystrophy (mdx) are both due to absence of the lows: (1) acute myofiber toxicity and gene transfer subsarcolemmal protein dystrophin. Recombinant adenoefficiency are both AdV dose-dependent, such that the virus vectors (AdV) are considered a promising means for therapeutic margin of safety is fairly narrow; (2) immunodelivering a functional dystrophin gene to muscle. Howsuppressive therapy (FK506) prevents immune-mediated ever, the usefulness of AdV for this purpose is limited by elimination of dystrophin-positive fibers but not the dosevector toxicity as well as immune-mediated elimination of dependent toxic effects; (3) at the optimal vector dosage infected fibers. In addition, studies to date of AdV-mediated and with effective immunosuppression, AdV-mediated dysdystrophin gene transfer have either failed to examine trophin minigene transfer is capable of alleviating the loss effects on muscle strength or been performed in immunoof force-generating capacity as well as histopathological logically immature neonatal animals with little baseline evidence of disease progression normally seen in adult abnormality of force-generating capacity. In the present mdx muscles over a 2-month period. These findings have study, AdV-mediated dystrophin gene transfer was perforimportant implications for the eventual application of AdVmed in adult mdx mice with pre-existent dystrophic pathomediated dystrophin gene transfer in DMD patients.

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“…These investigators therefore suggested that dystrophin may have a specific function in type lI fibers, which are capable of relatively higher rates of contraction compared to type I fibers. Hoffman and Gorospe [8] have presented an attractive interpretation for the observed differences between the effect of DMD on different fiber Despite a lack of definitive experimental evidene¢ indicative of a specific and early fiber-type involvement in the degenerative process characteristic of muscular dystrophy it is noteworthy that mdx muscle fibers are more vulnerable to necrosis, induced by lengthening contractions, compared to normal animals [9]. This observation is of particular significance in view of reports indicating that fast-twitch muscle fibers are preferentially damaged by eccentric contractions [10,11].…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of dystrophin in fast‐ and slow‐twitch mammalian skeletal muscle

Ho-Kim

Rogers

1992

FEBS Letters

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The relative tissue content of dystrophin has been evaluated in the slow‐twitch soleus (primarily type I fibers) and fast‐twitch vastus lateralis (primarily type IIb filbers) muscles of the rat and mouse, as well as in human biopsy samples from the vastus lateralis and gluteus maximus muscles, using a sensitive immunochemical assay. The dystrophin content of the soleus muscle was approximately twofold higher than in the vastus lateralis muscle. This difference is not entirely explained by the higher total sarcolemmal surface of the smaller soleus muscle type I fibers, and is therefore attributed to a higher content of dystrophin in the type I fibers compared to type II fibers, PCR analysis of the dystrophin transcript levels in the two muscle types indicated no significant differences. Analysis of human muscle biopsies revealed a twofold higher dystrophin content in the vastus lateralis muscle compared to the gluteus maximum muscle. It is concluded that the tissue content of dystrophin may vary significantly among physiologically different skeletal muscle types.

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Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions

Cited by 210 publications

References 24 publications

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice

Quantitative analysis of dystrophin in fast‐ and slow‐twitch mammalian skeletal muscle

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