New mouse model of Duchenne Muscular Dystrophy (mdx/mTRKO) now available at JAX

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Recently, the Blau laboratory developed a new dystrophic mouse model with impaired telomerase function (mdx/mTRKO) that recapitulates the skeletal muscle degeneration and cardiorespiratory failure seen in Duchenne Muscular Dystrophy (DMD) patients culminating in early death.) (Sacco et al., Cell, 2010, Mourkioti et al., Nature Cell Biology, 2013). The murine model was developed based on the hypothesis that a crucial difference between mice and humans is the length of their telomeres. Our findings substantiate that telomere length in conjunction with dystrophin plays a key role in the etiology of DMD.

By generation 2, mdx/mTRG2 mice manifest a profound loss of muscle force, poor performance on a treadmill, increased serum creatine kinase (CK) levels, accumulation of fibrosis and calcium deposits within skeletal muscle …

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Tackling ischemia to treat DMD

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In a recent publication Nelson et al proposed to use PDE5 inhibitors to treat DMD.

 

Duchenne Muscular Dystrophy (DMD) is a fatal progressive disease that affects about one in 3500 boys. DMD is caused by mutations in dystrophin that yield to protein loss. As a result, DMD myofibers are more susceptible to contraction-induced injury, leading to multiple cycles of muscle degeneration and regeneration and muscle fibrosis. Although great progress has been made toward the identification of new therapies for DMD, only glucocorticoids, such as prednisone and deflazacort, are currently approved, and have been shown to result in some benefit for DMD patients.

 

Multiple promising therapeutic approaches for DMD that had great efficacy in cell culture and animal models sadly fell short …

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Announcing the 2nd Cancer Cachexia Conference: Evolving Mechanisms and Therapies

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2nd Cancer Cachexia Conference:  Evolving Mechanisms and Therapies
Montreal, Canada
September 26-28, 2014

On behalf of the conference organizing committee, we are pleased to announce the second international meeting devoted to cancer cachexia. This conference is organized under a similar format as the previous seven cachexia conferences, but with an emphasis on a scientific program focused on teaching the clinical manifestations of cachexia in cancer, discussing the molecular mechanisms leading to weight loss and fatigue in cancer patients, identifying common and distinct pathways between cancer and other atrophy conditions, elucidating potential biomarkers, discovering therapeutic targets, and discussing current status of clinical trials, with the intent that such information can be used to better understand how to reverse or prevent the …

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Targeting skeletal muscle to treat SBMA

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Two recent reports by Cortes et al. and Lieberman et al. reveal a novel role of skeletal muscle on SBMA pathology and opens new avenues for alternative therapies against motor neuron disorders.

 

Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disorder characterized by primary motor neuron degeneration and muscle weakness. SBMA is caused by an aberrant elongation of a CAG repeat in the androgen receptor (AR) gene. Although SBMA has been traditionally considered a primary motor neuron disease, the fact that SBMA patients exhibit features of myopathy (Katsuno et al., 2012), and  that SBMA mouse models develop early myopathy and a pronounced delay on the  motor neuron pathology (Yu et al., 2006) indicate that skeletal …

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Forever young muscle.

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Under normal conditions skeletal muscle satellite cells (muSCs) are in a quiescent state, but when stimulated by damage, they re-enter the cell cycle to generate new fibers or self-renew to reconstitute the muSC pool. During aging muSC mediated regeneration is deeply impaired, leading to loss of skeletal muscle mass and strength (sarcopenia). Previous publications have suggested that changes in the aged muscle microenvironment lead to muSC malfunction and that a younger environment can reverse this process. Three recent publications are challenging this dogma by defining a muSC intrinsic mechanism that drives geriatric muSCs into a deep and irreversible state of senescence.

 

The groups lead by Pura Muñoz-Cánoves, Helen M Blau and Bradley B Olwin describe in three independent …

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Closing the calcium gates to treat stress induced arrhythmias.

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Much of what we know about the cardiac Ryanodine receptor (RyR2) relates to its role in excitation-contraction (EC) coupling. During this process, cell membrane voltage-gated Ca2+channels are activated by depolarization and transport Ca2+ into the cytosol where it binds to the high-affinity Ca2+ activation sites of RyR2. When RyR2 channels open, a large amount of calcium travels from the sarcoplasmic reticulum (SR) lumen into the cytoplasm, leading to the activation of contractile proteins. However, RyR2 plays also a key role in regulating SR calcium levels. When the SR lumen levels of Ca2+ reach a certain threshold, RyR2 spontaneously releases it into the cytoplasm. This store overload-induced Ca2+ release (SOICR) can result in cytosolic Ca2+ waves and delayed afterpolarizations that may …

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A new tool for MDC1A research

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Today in Skeletal Muscle we publish novel research on congenital muscular dystrophy Type 1A (MDC1A). Soonsang Yoon and colleagues communicate the potential uses of immortalized, clonal lines of human MDC1A myogenic cells, in studies of the pathogenic mechanisms of MDC1A, and the development of therapeutic approaches for the disease.

The use of primary cultures of human MDC1A myogenic cells uncovers two key issues; donor numbers are low and the cells have limited replicative ability. In this research article, the authors demonstrate that immortalized clonal lines not only are more numerous in availability and retain their replicative ability, but they also display a marked increase in caspase activity – a pathological change that is observed in primary cell …

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Rb1 loss modifies, but does not initiate, alveolar rhabdomyosarcoma

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The latest research article published in Skeletal Muscle by lead authors Ken Kikuchi , Eri Taniguchi and colleagues, focuses on Rhabdomyosarcoma, a childhood muscle cancer. Co-author Charles Keller describes the importance of deciphering the exact role of Rb1 in this disease and explains how their study will inform future research on this topic:

 Childhood muscle cancer (rhabdomyosarcoma) can be a devastating disease when invasive or metastatic, and yet being relatively rare its (diverse) developmental origins are only recently being elucidated.” Keller references two recent articles published in Cancer Cell; ‘The not-so-skinny on muscle cancer’ and ‘New Insights into the Origin and the Genetic Basis of Rhabdomyosarcomas’ for further information. “An interesting aspect is that cell-of-origin and

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MG53: Membrane mender or insulin signaling meddler?

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Just published in Skeletal Muscle is a Commentary article by Levy, Campbell and Glass which discusses a recent publication by Song et al., showing that MG53, a muscle-specific protein, has E3 ubiquitin ligase activity that targets the insulin receptor and insulin receptor substrate 1 for degradation. As MG53-null mice are protected from high-fat diet-induced elevations in body weight, blood pressure, and serum cholesterol and triglyceride levels – the hallmarks of Metabolic Syndrome – it appears that MG53 is a key player in mediating systemic metabolic changes. Conversely, transgenic mice that overexpress MG53 display the hallmarks of metabolic syndrome in the absence of a high-fat diet. This is a particularly unexpected finding, as MG53 had previously been characterized as a …

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Muscular Dystrophy beware, Superhealing MRL mice are here!

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 Murphy Roths Large (MRL) mice are an inbred mouse strain that has enhanced healing. This remarkable ability was first noted by researchers who observed that MRL mice could heal ear hole punch wounds seamlessly  – they regenerated cartilage, hair follicles, skin and blood vessels without scarring. Decreased fibrosis, altered inflammatory response, reduced apoptosis, increased proliferation, improved remodeling and enhanced stem cell function have all been suggested to explain the rapid healing of the MRL mice. To further complicate the identification of a mechanism for enhanced healing in these mice, over 40 different genetic loci have been associated with aspects of this unusual phenotype.

In the present study, Heydemann and colleagues bred MRL mice with mice lacking gamma-sarcoglycan, …

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