A critical evaluation of resting intracellular free calcium regulation in dystrophic mdx muscle

Hopf, F. Woodward; Turner, Paul; Denetclaw, Wilfred F.; Reddy, P. Jagan Mohan; Steinhardt, Richard A.

doi:10.1152/ajpcell.1996.271.4.c1325

Cited by 116 publications

(85 citation statements)

References 45 publications

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“…Our finding of a decreased sensitivity of the Ca 2ϩ release channel (when stimulated by caffeine) is in contrast to previous reports of normal electrically elicited Ca 2ϩ transients in muscles from mdx mice (4,14,35). Data on caffeine-induced contraction in saponinskinned single fibers from mdx mice are conflicting, with either an increase or decrease in the amplitude of caffeine-induced contraction being reported (8,33).…”

Section: Discussioncontrasting

confidence: 99%

Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice

Plant

Lynch

2003

American Journal of Physiology-Cell Physiology

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Dystrophin is absent in muscle fibers of patients with Duchenne muscular dystrophy (DMD) and in muscle fibers from the mdx mouse, an animal model of DMD. Disrupted excitation-contraction (E-C) coupling has been postulated to be a functional consequence of the lack of dystrophin, although the evidence for this is not entirely clear. We used mechanically skinned fibers (with a sealed transverse tubular system) prepared from fast extensor digitorum longus muscles of wild-type control and dystrophic mdx mice to test the hypothesis that dystrophin deficiency would affect the depolarization-induced contractile response (DICR) and sarcoplasmic reticulum (SR) function. DICR was similar in muscle fibers from mdx and control mice, indicating normal voltage regulation of Ca2+ release. Nevertheless, rundown of DICR (<50% of initial) was reached more rapidly in fibers from mdx than control mice [control: 32 ± 5 depolarizations ( n = 14 fibers) vs. mdx: 18 ± 1 depolarizations ( n = 7) before rundown, P < 0.05]. The repriming rate for DICRs was decreased in fibers from mdx mice, with lower submaximal DICR observed after 5, 10, and 20 s of repriming compared with fibers from control mice ( P < 0.05). SR Ca2+ reloading was not different in fibers from control and mdx mice, and no difference was observed in SR Ca2+ leak. Caffeine (2–7 mM)-induced contraction was diminished in fibers from mdx mice compared with control ( P < 0.05), indicating depressed SR Ca2+ release channel activity. Our findings indicate that fast fibers from mdx mice exhibit some impairment in the events mediating E-C coupling and SR Ca2+ release channel activity.

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Section: Discussioncontrasting

confidence: 99%

Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice

Plant

Lynch

2003

American Journal of Physiology-Cell Physiology

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“…Changes of Ca 2ϩ channel activities or appearance of novel forms of Ca 2ϩ leak channels, notably of stretch-activated Ca 2ϩ channels, have been reported (18,19). In addition, tetrodotoxin-sensitive spontaneous contractile activity of myotubes in culture exacerbates the stimulated Ca 2ϩ increases (12,13). We confirmed these observations since in more mature cultures (day 11) characterized by frequent spontaneous contractions, the peak increases caused by KCl was found to be significantly higher, both in the cytosol and in the sub-plasmalemmal space.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that the defect in Ca 2ϩ homeostasis is exacerbated in mdx cells upon application of mechanical stress (12,13). A simple and physiological way to test this hypothesis is to prolong the time in culture.…”

Section: Subcellular Ca 2ϩ Handling Alterations In MDX Myotubes 4649mentioning

confidence: 99%

“…We addressed this issue directly by using the strategy of targeted aequorin that we previously developed and used to analyze Ca 2ϩ handling in different types of cells ranging from cell lines to primary cultures of neurons or rat skeletal myotubes (8 -11). To evaluate the importance of mechanical stress as a key factor in the development of muscle degeneration (12,13), analysis of [Ca 2ϩ ] homeostasis at the subcellular levels was carried out both at day 7 of culture (when spontaneous contractions are minimal) and in older cultures (day 11), i.e. in cells harboring a more mature contractile machinery that undergo frequent contractions.…”

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confidence: 99%

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Alteration in Calcium Handling at the Subcellular Level inmdx Myotubes

Robert

Massimino

Tosello

et al. 2001

Journal of Biological Chemistry

143

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] occurring in the mitochondrial matrix of mdx myotubes are significantly larger than in controls upon KCl-induced depolarization or caffeine application. The augmented response of mitochondria precedes the alterations in the Ca 2؉ responses of the cytosol and of the cytoplasmic region beneath the membrane, which become significant only at a later stage of myotube differentiation. Taking into account the key role played by mitochondria Ca 2؉ handling in the control of cell death, our data suggest that mitochondria are potential targets of impaired Ca 2؉ homeostasis in muscular dystrophy.Although it is well established that the lack of dystrophin expression is the primary genetic defect in Duchenne's muscular dystrophy (DMD), 1 the mechanism leading to progressive muscle damage is still largely unknown (1). It has been suggested that an elevation of cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] c ), under resting conditions, and a concurrent activation of Ca 2ϩ -dependent proteases may represent the mechanistic link between the genetic defect and the DMD phenotype (2). The differences in [Ca 2ϩ ] c between normal and dystrophic muscles have been found also in myotubes and in the classical animal model of the disease, the mdx mouse. Several groups (3, 4), however, have been unable to confirm these data, and the question remains controversial.Evidence has been accumulated over the last few years indicating that a key aspect of the Ca 2ϩ signaling pathway is represented by its spatial and temporal complexity. Localized changes in the cytosol, much larger than those occurring in the bulk cytosol, are known to occur close to the mouth of Ca 2ϩ channels, and these localized events are pivotal in triggering important cellular events such as secretion, gene expression, and metabolic activation. In this respect, mitochondria represent a privileged sensor of local [Ca 2ϩ ] increases. Not only their Ca 2ϩ accumulation depends on microdomains of high Ca 2ϩ generated in their vicinity, but their capacity to take up Ca 2ϩ is essential to shape the kinetics of cytoplasmic Ca 2ϩ changes (5). Last, but not least, mitochondrial Ca 2ϩ accumulation results in activation of ATP production under physiological conditions (6) but leads to initiation of apoptotic signaling when excess Ca 2ϩ is taken up by the organelles (7). Taking into account the key role played by mitochondria Ca 2ϩ handling in the control of cell death, our data suggest that mitochondria are potential targets of impaired Ca 2ϩ homeostasis in muscular dystrophy.In this study, we tested the hypothesis that the differences in cytoplasmic [Ca 2ϩ ] in muscles lacking dystrophin might be amplified in specific cellular regions, in particular within the mitochondrial matrix. We addressed this issue directly by using the strategy of targeted aequorin that we previously developed and used to analyze Ca 2ϩ handling in different types of cells ranging from cell lines to primary cultures of neurons or rat skeletal myotubes (8 -11). To evaluate the importance of mechanical...

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“…There is some controversy about this Ca 2ϩ elevation (1,4). Some groups (5,6) showed that basal cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] c ) 1 was higher in dystrophic skeletal muscle cells relative to controls, whereas other laboratories (7,8) found that [Ca 2ϩ ] c was only increased under stress. To elucidate this contention, the redistribution of Ca 2ϩ into intracellular organelles should be examined.…”

Section: Exchanges During Kcl Depolarization These Newly Demonstratementioning

confidence: 99%

Mitochondrial Calcium Oscillations in C2C12 Myotubes

Challet

Maechler²,

Wollheim³

et al. 2001

Journal of Biological Chemistry

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A critical evaluation of resting intracellular free calcium regulation in dystrophic mdx muscle

Cited by 116 publications

References 45 publications

Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice

Depolarization-induced contraction and SR function in mechanically skinned muscle fibers from dystrophic mdx mice

Alteration in Calcium Handling at the Subcellular Level inmdx Myotubes

Mitochondrial Calcium Oscillations in C2C12 Myotubes

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