Myopathy as Possible Side-Effect of Cyclosporin

Goy, Jean‐Jácques; Stauffer, Jean‐Christophe; Déruaz, J. P.; Gillard, Daniele; Kaufmann, U; Küntzer, Thierry; Kappenberger, Lukas

doi:10.1016/s0140-6736(89)90147-5

Cited by 50 publications

(24 citation statements)

References 3 publications

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“…In this respect, our findings corroborate reports of a lack of change in the size and phenotype of skeletal muscle in normal weight-bearing rats administered lower dosages of CsA (24). This apparent dependence of calcineurin signaling on relative increases in muscle activation characteristics may also explain why transplant recipients administered therapeutic dosages of this immunosuppressant during their recovery from surgery are unable to regain losses in skeletal muscle mass and strength related to pre-and post-surgical bed rest (25).…”

Section: Resultssupporting

confidence: 89%

Calcineurin Is Required for Skeletal Muscle Hypertrophy

Dunn

Burns

Michel

1999

Journal of Biological Chemistry

247

269

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Molecular signaling pathways linking increases in skeletal muscle usage to alterations in muscle size have not been identified. In the present study, we tested the hypothesis that calcineurin, a calcium-regulated phosphatase recently implicated in the signaling of some forms of cardiomyopathic growth, is required to induce skeletal muscle hypertrophy and muscle fiber type conversions associated with functional overload in vivo. Administration of the specific calcineurin inhibitors cyclosporin (CsA) or FK506 to mice, for which the fast plantaris muscle was overloaded for 1-4 weeks, prevented the rapid doubling of mass and individual fiber size and the 4 -20-fold increase in the number of slow fibers that characterize this condition. CsA treatment influenced the expression of muscle myofibrillar protein genes in a way reflective of fiber phenotype transformations but only in the long term of the overload condition, suggesting that the control of this growth response by calcineurin is not limited to the transcriptional activation of these muscle-specific genes. Clinically, these results provide insight to the post-surgical muscle wasting and weakness observed in recovering transplant recipients administered therapeutic dosages of these immunosuppressants.The amount and type of contractile proteins incorporated into the myofibrils of skeletal muscle fibers are major determinants of the size, strength, and speed of these cells (1). To date, the molecular events linking muscle usage to the cellular expression and accumulation of these proteins are unknown. Recently, calcineurin, a cytoplasmic calcium-regulated phosphatase implicated in the pathogenesis of hypertrophic cardiomyopathy (2, 3), has emerged as a possible candidate in the signaling of skeletal muscle cellular growth and the fiber type transformations (4) of these cells. Calcineurin is an enticing prospect as a regulatory enzyme in this signaling because its selective activation of NF-AT (nuclear factor of activated T cells) transcription factors in response to sustained increases in intracellular calcium concentrations (5) is reminiscent of calcium fluctuations provoked by the activation of muscle cells during extensive contractile work (4, 6).Typically, a fast weight-bearing muscle subjected to the functional loss of its synergists will compensate by displaying within 2-4 weeks a doubling of mass and individual fiber sizes and an increase in strength (7,8). A muscle overloaded in this manner will also contract more slowly as a result of rapid fiber type transformations characterized by an increase in the number of fibers exhibiting slower, more energy-efficient contractile and calcium-handling proteins (7-9). In rodent fast muscle, the myosin heavy chain (MHC) 1 enzyme component of the major contractile protein myosin displays a conversion pattern in response to overload that follows from the fastest to the slowest isoform in the order MHC IIb 3 IIx 3 IIa 3 I/slow. The signaling of these adaptations may well be mediated by calcineurin since most of the fun...

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Section: Resultssupporting

confidence: 89%

Calcineurin Is Required for Skeletal Muscle Hypertrophy

Dunn

Burns

Michel

1999

Journal of Biological Chemistry

247

269

View full text Add to dashboard Cite

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“…In organ transplant patients, CsA is therapeutically used at a daily dose of 200 -250 mg and the treatment usually lasts from several weeks to several months (47,5). Clinically relevant muscular disorders associated with CsA are generally mild and develop on chronic treatment (5).…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A Inhibits Creatine Uptake by Altering Surface Expression of the Creatine Transporter

Tran

Dai

Sarkar

2000

Journal of Biological Chemistry

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The immunosuppressive drug cyclosporin A (CsA) inhibited the hCRT-1 cDNA-induced creatine uptake in Xenopus oocytes and the endogenous creatine uptake in cultured C 2 C 12 muscle cells in a dose-and time-dependent manner. FK506, another potent immunosuppressant, was unable to mimic the effect of CsA suggesting that the inhibitory effect of CsA was specific. To delineate the mechanism underlying, we investigated the effect of CsA on the K m and V max of creatine transport and also on the cell surface distribution of the creatine transporter. Although CsA treatment did not affect the K m (20 -24 M) for creatine, it significantly decreased the V max of creatine uptake in both oocytes and muscle cells. CsA treatment reduced the cell surface expression level of the creatine transporter in the muscle cells by ϳ60% without significantly altering its total expression level, and the reduction in the cell surface expression paralleled the decrease in creatine uptake. Taken together, our results suggest that CsA inhibited creatine uptake by altering the surface abundance of the creatine transporter. We propose that CsA impairs the targeting of the creatine transporter by inhibiting the function of an associated cyclophilin, resulting in an apparent loss in surface expression of the creatine transporter. Our results also suggest that prolonged exposure to CsA may result in chronically creatine-depleted muscle, which may be a cause for the development of CsA-associated clinical myopathies in organ transplant patients.

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“…(7) This may also begin to explain why transplant patients treated with CsA show severe skeletal muscle weakness. (43) Control of skeletal muscle hypertrophy by calcineurin IGFs are potent inducers of skeletal muscle hypertrophy in vivo and in vitro, acting by stimulating expression of L-type Ca 2 channels, which increase near-membrane Ca 2 concentrations. (44,45) Evidence for an essential role of calcineurin activation in IGF1-mediated skeletal myocyte hypertrophy has come from the finding that expression of an IGF1 expression vector in cultured rat myoblasts or exposure to IGF1 results in dramatic hypertrophy accompanied by upregulation of calcineurin expression and its nuclear localization.…”

Section: Control Of Skeletal Muscle Differentiation and Regeneration mentioning

confidence: 99%

Remodeling muscles with calcineurin

2000

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Ca2+ signaling plays a central role in hypertrophic growth of cardiac and skeletal muscle in response to mechanical load and a variety of signals. However, the mechanisms whereby alterations in Ca2+ in the cytoplasm activate the hypertrophic response and result in longterm changes in muscle gene expression are unclear. The Ca2+, calmodulin‐dependent protein phosphatase calcineurin has been proposed to control cardiac and skeletal muscle hypertrophy by acting as a Ca2+ sensor that couples prolonged changes in Ca2+ levels to reprogramming of muscle gene expression. Calcineurin also controls the contractile and metabolic properties of skeletal muscle by activating the slow muscle fiber‐specific gene program, which is dependent on Ca2+ signaling. Transcription factors of the NFAT and MEF2 families serve as endpoints for the signaling pathways whereby calcineurin controls muscle hypertrophy and fiber‐type. We consider these findings in the context of a model for Ca2+‐regulated gene expression in muscle cells and discuss potential implications of these findings for pharmacologic modification of cardiac and skeletal muscle function. BioEssays 22:510–519, 2000. © 2000 John Wiley & Sons, Inc.

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Myopathy as Possible Side-Effect of Cyclosporin

Cited by 50 publications

References 3 publications

Calcineurin Is Required for Skeletal Muscle Hypertrophy

Calcineurin Is Required for Skeletal Muscle Hypertrophy

Cyclosporin A Inhibits Creatine Uptake by Altering Surface Expression of the Creatine Transporter

Remodeling muscles with calcineurin

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