Small‐caliber skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression

Karpati, George; Carpenter, Stirling; Opitz, John M.

doi:10.1002/ajmg.1320250407

Cited by 135 publications

(60 citation statements)

References 15 publications

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“…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).…”

Section: Discussionmentioning

confidence: 92%

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

Porter

Merriam

Gong

et al. 2003

Journal of Experimental Biology

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SUMMARYThe M-line and its associated creatine kinase (CK) M-isoform (CK-M) are ubiquitous features of skeletal and cardiac muscle. The M-line maintains myosin myofilaments in register, links the contractile apparatus to the cytoskeleton for external force transfer and localizes CK-based energy storage and transfer to the site of highest ATP demand. We establish here that the muscle group responsible for movements of the eye, extraocular muscle (EOM),is divergent from other striated muscles in lacking both an M-line and its associated CK-M. Although an M-line forms during myogenesis, both in vivo and in vitro, it is actively repressed after birth. Transcripts of the major M-line structural proteins, myomesin 1 and myomesin 2, follow the same pattern of postnatal downregulation, while the embryonic heart-specific EH-myomesin 1 transcript is expressed early and retained in adult eye muscle. By immunocytochemistry, myomesin protein is absent from adult EOM sarcomeres. M-line suppression does not occur in organotypic co-culture with oculomotor motoneurons, suggesting that the mechanism for suppression may lie in muscle group-specific activation or workload patterns experienced only in vivo. The M-line is, however, still lost in dark-reared rats, despite the developmental delay this paradigm produces in the visuomotor system and EOMs. EOM was low in all CK isoform transcripts except for the sarcomeric mitochondrial (Ckmt2) isoform. Total CK enzyme activity of EOM was one-third that of hindlimb muscle. These findings are singularly unique among fast-twitch skeletal muscles. Since EOM exhibits isoform diversity for other sarcomeric proteins, the M-line/CK-M divergence probably represents a key physiological adaptation for the unique energetics and functional demands placed on this muscle group in voluntary and reflexive eye movements.

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Section: Discussionmentioning

confidence: 92%

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

Porter

Merriam

Gong

et al. 2003

Journal of Experimental Biology

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“…19,20 It is important to emphasize that the increase in myofiber CSA after myostatin inhibition 19,20 did not increase the susceptibility to contraction-mediated injury because it contradicts the supposition that larger muscle fibers are more susceptible to contraction-mediated injury and that smaller caliber muscle fibers are protected from the dystrophic pathology. 2,38,39 In conclusion, myostatin inhibition with the novel antibody PF-354 attenuated the progression of the pathophysiology of the diaphragm of mdx mice when initiated early and before the onset of major muscle fiber degeneration. The findings highlight the therapeutic potential of pharmacological inhibition of myostatin in muscular dystrophy.…”

Section: Myostatin Inhibition Does Not Increase the Susceptibility Ofmentioning

confidence: 87%

Antibody-Directed Myostatin Inhibition Improves Diaphragm Pathology in Young but not Adult Dystrophic mdx Mice

Murphy

Ryall

Snell

et al. 2010

The American Journal of Pathology

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Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle wasting and weakness, leading to premature death from respiratory and/or cardiac failure. A clinically relevant question is whether myostatin inhibition can improve function of the diaphragm, which exhibits a severe and progressive pathology comparable with that in DMD. We hypothesized that antibody-directed myostatin inhibition would improve the pathophysiology of diaphragm muscle strips from young mdx mice (when the pathology is mild) and adult mdx mice (when the pathology is quite marked). Five weeks treatment with a mouse chimera of anti-human myostatin antibody (PF-354 , 10 mg/kg/week) increased muscle mass (P < 0.05) and increased diaphragm median fiber cross-sectional area (CSA, P < 0.05) in young C57BL/10 and mdx mice , compared with salinetreated controls. PF-354 had no effect on specific force (sP o , maximum force normalized to muscle CSA) of diaphragm muscle strips from young C57BL/10 mice, but increased sP o by 84% (P < 0.05) in young mdx mice. In contrast, 8 weeks of PF-354 treatment did not improve muscle mass , median fiber CSA , collagen infiltration , or sP o of diaphragm muscle strips from adult mdx mice. PF-354 antibody-directed myostatin inhibition completely restored the functional capacity of diaphragm strips to control levels when treatment was initiated early , but not in the later stages of disease progression , suggesting that such therapies may only have a limited window of efficacy for DMD and related conditions. (Am J

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“…The resulting increase of cytosolic [Ca 2ϩ ] would cause damage by activation of proteases and/or by increased oxidative stress, eventually leading to cell death (58). Specific muscles are spared by the disease, however, and these include the extraocular muscles (59) and the esophagus (60). In the case of extraocular muscle, the adaptive mechanism appears to be at least in part linked to up-regulation of the closely related utrophin, yet selected fibers are resistant to death even in mice lacking both dystrophin and utrophin (61).…”

Section: Multiple Effects Of Bupivacaine On Mitochondrial Energymentioning

confidence: 99%

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Irwin

Fontaine

Agnolucci

et al. 2002

Journal of Biological Chemistry

163

114

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We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mM or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca 2؉ , release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca 2؉ dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role.

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Small‐caliber skeletal muscle fibers do not suffer deleterious consequences of dystrophic gene expression

Cited by 135 publications

References 15 publications

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

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

Antibody-Directed Myostatin Inhibition Improves Diaphragm Pathology in Young but not Adult Dystrophic mdx Mice

Bupivacaine Myotoxicity Is Mediated by Mitochondria

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