Improved Contractile Function of the mdx Dystrophic Mouse Diaphragm Muscle after Insulin-Like Growth Factor-I Administration

Gregorevic, Paul; Plant, David R.; Leeding, Kerri S.; Bach, Leon A.; Lynch, Gordon S.

doi:10.1016/s0002-9440(10)64502-6

Cited by 108 publications

(112 citation statements)

References 43 publications

(55 reference statements)

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“…9 Taking into account the pivotal role of calcineurin in maintaining the slow-twitch program and the phenotype-dependent expression of chloride channels, 19,46 it is feasible that the CsA treatment can increase gCl by reducing the proportion of fibers belonging to the slow phenotype, as supported by the observation that the low percentage of EDL fibers co-expressing the slow isoform of myosin heavy chain, was further reduced in CsA-treated mice. However, although this mechanism may account for the CsA effect on gCl of mdx DIA, in which a compensatory fast-to-slow phenotype shift has been described, albeit nonunanimously, 47,48 it cannot explain the drug effect in mdx EDL muscle because we confirmed that no functionally significant phenotype transition occurs in this fast muscle in response to either genotype or exercise. 29 We previously hypothesized, 9 that the decrease of gCl induced by exercise in EDL muscle fibers might be related to a short-term action of proinflammatory cytokines, produced in response to the damaging effect of exercise, on the function of chloride channel.…”

Section: Csa Exerts Different Effects On Functional Cellular Parametementioning

confidence: 51%

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

Nico

Liantonio

et al. 2005

The American Journal of Pathology

114

129

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Chronic inflammation is a secondary reaction of Duchenne muscular dystrophy and may contribute to disease progression. To examine whether immunosuppressant therapies could benefit dystrophic patients, we analyzed the effects of cyclosporine A (CsA) on a dystrophic mouse model. Mdx mice were treated with 10 mg/kg of CsA for 4 to 8 weeks throughout a period of exercise on treadmill, a protocol that worsens the dystrophic condition. The CsA treatment fully prevented the 60% drop of forelimb strength induced by exercise. A significant amelioration (P < 0.05) was observed in histological profile of CsA-treated gastrocnemius muscle with reductions of nonmuscle area (20%), centronucleated fibers (12%), and degenerating area (50%) compared to untreated exercised mdx mice. Consequently, the percentage of normal fibers increased from 26 to 35% in CsA-treated mice. Decreases in creatine kinase and markers of fibrosis were also observed. By electrophysiological recordings ex vivo, we found that CsA counteracted the decrease in chloride conductance (gCl), a functional index of degeneration in diaphragm and extensor digitorum longus muscle fibers. However, electrophysiology and fura-2 calcium imaging did not show any amelioration of calcium homeostasis in extensor digitorum longus muscle fibers. No significant effect Duchenne muscular dystrophy (DMD) is a fatal genetic disorder for which no definitive cure is available. The X-linked mutation of the dystrophin gene leads to the absence of dystrophin in skeletal muscle fibers, a biochemical defect also observed in the mdx mouse, the murine phenotype of DMD. 1 Dystrophin is a subsarcolemmal protein involved in the link between the contractile machinery and the extracellular matrix. It is generally accepted that the absence of dystrophin weakens the sarcolemma and impairs the transduction of the mechanical signal imposed by the contraction. This leads to a complex and still not fully understood network of interconnected pathogenic events responsible for progressive muscle degeneration; these events involve the increased entrance of calcium, the activation of proteases, and the occurrence of a functional ischemic state. [1][2][3][4] Recent evidence suggests that a chronic inflammatory state is a secondary reaction that strongly contributes to the progression of the pathology. A significant overexpression of inflammatory and immune response genes has been described by microarray in muscle of dystrophic subjects. 5,6 Also, activated helper and cytotoxic T cells have been found to be present in higher number in muscles of dystrophic mdx mice and to promote pathology in this phenotype. 7 According to this view, immunoSupported by Telethon-Italy (to project no. 1150) and the Association Franç ais Contre les Myopathies (as part of postdoctoral fellowships to

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Section: Csa Exerts Different Effects On Functional Cellular Parametementioning

confidence: 51%

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

Nico

Liantonio

et al. 2005

The American Journal of Pathology

114

129

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“…We have demonstrated similar effects in previous studies, where recombinant IGF-I protein was delivered to mice at an identical dose via mini-osmotic pumps. 28,29 In these studies, systemic IGF-I protein administration induced morphological and functional changes, but IGF-I levels, as measured by RIA, were elevated in blood serum, but not in diaphragm or limb muscles. 28,29 Given its therapeutic potential to enhance restoration of muscle structure and function after damage, closer examination of the mechanisms of action of IGF-I at this dose and route of delivery is warranted.…”

Section: Discussionmentioning

confidence: 89%

“…28,29 In these studies, systemic IGF-I protein administration induced morphological and functional changes, but IGF-I levels, as measured by RIA, were elevated in blood serum, but not in diaphragm or limb muscles. 28,29 Given its therapeutic potential to enhance restoration of muscle structure and function after damage, closer examination of the mechanisms of action of IGF-I at this dose and route of delivery is warranted. It should be noted that the hastened functional recovery after electrotransfer could be directly related to higher IGF-I levels in regenerating muscle.…”

Section: Discussionmentioning

confidence: 89%

Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury

Schertzer

Lynch

2006

Gene Ther

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“…56,57 Postnatal treatment of mdx mice with subcutaneous IGF-1 demonstrated increased specific force and resistance to fatigue of diaphragm muscles. 58 Clinical trials of IGF-1 isoforms have not yet been attempted in DMD. However, recombinant human IGF-1 plus IGF-1 binding protein 3 is currently being studied in a phase II trial of myotonic muscular dystrophy (NCT00577577; clinical trials.gov).…”

Section: Modulation Of Muscle Growth and Regenerationmentioning

confidence: 99%

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Wagner

2008

Neurotherapeutics

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Summary:Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy. The cornerstones of current treatment include corticosteroids for skeletal muscle weakness, afterload reduction for cardiomyopathy, and noninvasive ventilation for respiratory failure. With these interventions, patients are walking and living longer. However, the current status is still far from adequate. Increased private and federal funding of studies in Duchenne muscular dystrophy has led to a large number of novel agents with propitious therapeutic potential. These include agents that modify dystrophin expression, increase muscle growth and regeneration, and modulate inflammatory responses. Many of these agents are already in clinical trials. Challenges to the development of additional novel therapeutics exist, including lack of validated animal models and lack of adequate biomarkers as surrogate endpoints. However, these challenges are not insurmountable and the next decade will likely see meaningful, new treatment options introduced into the clinical care of patients with Duchenne muscular dystrophy.

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Improved Contractile Function of the mdx Dystrophic Mouse Diaphragm Muscle after Insulin-Like Growth Factor-I Administration

Cited by 108 publications

References 43 publications

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

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