Na+−Ca2+ EXCHANGE IN LIMB MUSCLES OF DYSTROPHIC (C57 BL/6J dy2J/dy2J) MICE

Noireaud, Jacques; Léoty, Claude

doi:10.1113/expphysiol.1989.sp003242

Cited by 6 publications

(2 citation statements)

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“…These results are yet another indirect line of evidence that increased Ca 2ϩ entry occurs in myofibers from NCX1 TG mice, given that its known electrogenic properties would hyperpolarize the membrane when acting in reverse mode. Indeed, dystrophic fibers from mice lacking laminin 2 displayed membrane hyperpolarization due to presumed reverse-mode NCX activity (46). NCX1 transgenic mice develop progressive muscle pathology in their limbs.…”

Section: Resultsmentioning

confidence: 99%

Na⁺ Dysregulation Coupled with Ca²⁺ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Burr

Millay

Park

et al. 2014

Molecular and Cellular Biology

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f Unregulated Ca 2؉ entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na ؉ -Ca 2؉ exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in ␦-sarcoglycan (Sgcd ؊/؊ ), Dysf ؊/؊ , and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd ؊/؊ mice. Measured increases in baseline Na ؉ and Ca 2؉ in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca 2؉ influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca 2؉ levels. Indeed, Atp1a2 ؉/؊ (encoding Na ؉ -K ؉ ATPase ␣2) mice, which have reduced Na ؉ clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na ؉ -K ؉ ATPase inhibitor digoxin. Treatment of Sgcd ؊/؊ mice with ranolazine, a broadly acting Na ؉ channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology. M uscular dystrophy (MD) is characterized by myofiber degeneration that results in muscle loss, functional impairment, and eventually death. MD is generally caused by genetic mutations in genes encoding proteins that are either part of the membrane-stabilizing dystrophin-glycoprotein complex (DGC) or otherwise impact some aspect of sarcolemmal integrity and membrane channel activity (1). Such alterations cause enhanced Ca 2ϩ entry through microtears or Ca 2ϩ channels/exchangers (2). Downstream consequences of increased Ca 2ϩ entry include altered signaling, calpain activation leading to unregulated intracellular protein degradation, and induction of necrosis through opening of the mitochondrial permeability transition pore with mitochondrial rupture (3, 4). However, the hypothesis that Ca 2ϩ elevations directly induce myofiber necrosis and lead to MD is controversial (2). While some groups have indeed reported global or even subsarcolemmal increases in Ca 2ϩ in dystrophic myofibers (5-10), such measurements are often technically difficult, which may be the reason why other studies have not observed a significant increase (11-13). Recent studies in transgenic (TG) mice have supported the Ca 2ϩ hypothesis of disease. For example, overexpression of dominant-negative transient receptor potential canonical 6 (dnTRPC6) or dnTRPV2 was sufficient to abrogate the dystrophic phenotype in mice by inhibiting a type of storeoperated Ca 2ϩ entry that characterizes these channels (14, 15). TRPC3 overexpression in skeletal muscle, which dramatically enhanced Ca 2ϩ entry, was sufficient to induce MD in mice (14). Finally, overexpre...

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Section: Resultsmentioning

confidence: 99%

Na⁺ Dysregulation Coupled with Ca²⁺ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Burr

Millay

Park

et al. 2014

Molecular and Cellular Biology

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“…The role of intracellular Ca 2+ -overload in the pathogenesis of muscular disorder is supported by observations that exercise in dystrophic mdx mice enhanced Ca 2+influx, impaired Ca 2+ -homeostasis and aggravated this disease [221]. It should be pointed out that the increased Ca 2+influx in myopathic muscle may be occurring through SOCE channels [192,216,222], voltage-independent Ca 2+ -leakage channels [223], voltage-dependent Ca 2+ -channels [189] and Na + /Ca + exchange system [154,155,224,225] in the SL membrane. Since the SL phospholipase A 2 [190] and adenylate cyclase activities [226] are increased in dystrophic muscles, these signal transduction systems have also been suggested to participate in enhancing Ca 2+ -entry into muscle fiber.…”

Section: Mechanisms Of Subcellular Ca 2+ -Handling Abnormalities In Dystrophic Musclementioning

confidence: 93%

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Bhullar¹,

Nusier²,

Shah³

et al. 2021

Journal of Molecular and Clinical Medicine

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Myosin isoforms in hindlimb muscles of normal and dystrophic (ReJ129 dy/sol;dy) mice

et al. 1992

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Myosin isoform expression was studied in hindlimb muscles of control (Dyi Dy) and dystrophic (dyldy) mice of the ReJ129 strain during postnatal development. Three myosin heavy chain isoforms (fast ll-B MHC, neonatal MHC, and slow or I MHC) were identified using monoclonal antibodies.Only original fibers, i.e., fibers formed during fetal life, were studied. Necrotic and regenerating fibers were excluded. The disappearance of neonatal MHC was found to be delayed in all muscles of dystrophic mice, except the soleus. The fraction of fibers containing I MHC was similar in control and dystrophic animals at all ages, except during the third postnatal week. The developmental increase in the fraction of fibers expressing ll-B MHC was interrupted in dystrophic mice by two marked declines. The first occurred during the second postnatal week at the beginning of the main wave of fiber necrosis, and the second occurred at between 30 and 90 postnatal days.

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Na⁺−Ca²⁺ EXCHANGE IN LIMB MUSCLES OF DYSTROPHIC (C57 BL/6J dy^2J/dy^2J) MICE

Cited by 6 publications

References 10 publications

Na⁺ Dysregulation Coupled with Ca²⁺ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Na⁺ Dysregulation Coupled with Ca²⁺ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Myosin isoforms in hindlimb muscles of normal and dystrophic (ReJ129 dy/sol;dy) mice

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Na+−Ca2+ EXCHANGE IN LIMB MUSCLES OF DYSTROPHIC (C57 BL/6J dy2J/dy2J) MICE

Cited by 6 publications

References 10 publications

Na+ Dysregulation Coupled with Ca2+ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Na+ Dysregulation Coupled with Ca2+ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

Myosin isoforms in hindlimb muscles of normal and dystrophic (ReJ129 dy/sol;dy) mice

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Na⁺−Ca²⁺ EXCHANGE IN LIMB MUSCLES OF DYSTROPHIC (C57 BL/6J dy^2J/dy^2J) MICE

Na⁺ Dysregulation Coupled with Ca²⁺ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Na⁺ Dysregulation Coupled with Ca²⁺ Entry through NCX1 Promotes Muscular Dystrophy in Mice