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

Read more]]>  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, a model for muscular dystrophy. Gamma-sarcoglycan is a part of the sarcoglycan complex of sarcolemmal transmembrane proteins, which interacts with dystrophin and stabilizes it at the sarcolemma. When the gene for gamma-sarcoglycan is mutated in human patients, it causes limb-girdle muscular dystrophy type 2C. Mice that are null for sarcoglycan develop muscular dystrophy and cardiomyopathy similar to these patients.

When the authors bred MRL mice with gamma-sarcoglycan-deficient mice, they found an improvement in cardiac function compared to gamma-sarcoglycan-deficient mice on the initial background (DBA/2J). They also observed an improvement in muscle pathology: fibrosis was decreased in both cardiac and skeletal muscle. Interestingly, Evans blue dye indicated that the MRL background does not protect against membrane leak. A genome-wide scan identified a region on chromosome 2 that associated with fibrosis of the heart, diaphragm and abdominal muscles. The exact mechanism by which the MRL background improves muscular dystrophy is still unknown. However, we can speculate that further work to identify the specific genes involved could potentially contribute towards  design of a therapy for muscular dystrophy.

 Visit the Skeletal Muscle homepage to read the full article.

 Posted on behalf of Jennifer R. Levy.

Read more]]> Cachexia severely limits therapeutic options in cancer patients, and is thought to cause about 20% of cancer deaths. Skeletal muscle mitochondria are emerging as critical mediators of muscle protein turnover during cancer cachexia. Using the severely cachectic Apc^Min/+ mice, White and colleagues examined the role of IL-6 on the regulation of mitochondrial remodeling/dysfunction that precedes muscle proteolysis during cachexia. The authors had previously shown that inhibition of IL-6 signaling can attenuate the progression of cachexia. In the current study, they treated Apc^Min/+ mice with an antibody against the IL-6 receptor and reduced the loss of mitochondrial biogenesis and content, compared to vehicle-treated mice. IL-6 inhibition also restored the altered mitochondrial fusion and reduced apoptosis observed in cachectic Apc^Min/+ mice.

Excitingly, the authors found that exercise-training has a protective effect on IL-6 overexpression-induced muscle wasting in Apc^Min/+ mice. Whereas IL-6 overexpression in sedentary animals decreased mitochondrial fusion protein expression and increased mitochondrial fission protein expression, IL-6 overexpressing mice that underwent 12 weeks of moderate treadmill training prevented these changes. Apoptosis, autophagy, and phosphorylation of FoxO, a potent regulator of muscle proteolysis, were also reduced in exercise-trained Apc^Min/+ mice. Taken together, this paper shows that IL-6 is a central regulator of altered mitochondrial biogenesis and fusion in early cachexia, and that IL-6 induced mitochondrial remodeling and proteolysis can be rescued with exercise training.

Tocilizumab, a monoclonal antibody that inhibits the IL-6 receptor, is currently approved for use in patients with rheumatoid arthritis. It is interesting to speculate that this therapy has potential to manage cancer cachexia as well.

Visit the Skeletal Muscle homepage to read the full article.

Posted on behalf of Jennifer R. Levy.

Read more]]> Myoblast differentiation is a process that is required for the regeneration of myofibres post injury. In old age this is impaired and contributes to the onset of sarcopenia, and the resulting loss of muscle mass and strength.

A research paper published last week in Skeletal Muscle explores the effects of IL-1α and TNF-α on myotube differentiation, and the signalling cascades through which they act. Despite the ongoing debate into whether pro-inflammatory cytokines have a positive or negative effect on muscle cell differentiation, the results from this article clearly demonstrate the anti-differentiation effects of IL-1α and TNF-α.

Trendelenburg et al. show that human myoblasts treated with IL-1α and TNF-α induce Activin A de novo synthesis via the TAK-1/p38/NFκB pathway. TAK-1 and p38 are both required for Activin A induction – with the inhibition of TAK-1 blocking both the increase in Activin A and the downstream activation of p38, and the inhibition of p38 resulting in increased differentiation. NFκB also contributes to Activin A induction, though inhibition of NFκB is less effective than inhibition of p38 in rescuing myoblast differentiation. This induction of Activin A then results in the activation of downstream Activin receptor signalling via SMAD2/3 transcription factors, and the inhibition of myoblast differentiation.

This study establishes the mechanism for an additional anti-muscle effect of cytokines – the blockade of differentiation by Activin A secretion” explain the authors. “The induction of Activin A by TNF-α and IL-1α may help to explain some of the phenotypes previously reported in aging animals, including humans”.

Visit the Skeletal Muscle homepage to read the article in full.

Read more]]> The start of 2012 marked one year since the launch of Skeletal Muscle. In January 2011, the journal set out to provide a home for the increasing amounts of research being conducted into skeletal muscle – from the genes responsible for muscular dystrophies, to the contribution of skeletal muscle to insulin and fatty acid signalling.

To mark this anniversary, Skeletal Muscle published an Editorial written by the journal’s Editors-in-Chief; Profs David Glass, Kevin Campbell and Michael Rudnicki. The Editorial, which can be read in full here, looks back over a successful first year, with 20 original research articles and 16 reviews being published, as well as the journal’s inclusion in PubMed. In this article, the Editors state “The bottom line is that this is truly a group endeavor; Skeletal Muscle is here for the scientist interested in this dynamic tissue.  Like its namesake, it can only gather strength with use and exercise – perhaps you can start by including us in your New Year’s resolution for 2012… to help grow the journal by your support.”

To view the journals aims and scope, or to submit an article, visit the Skeletal Muscle homepage.

Read more]]> It is well known that some forms of muscular dystrophies are caused by mutations in the genes coding for dystrophin and dysferlin – two proteins which both have important roles in the correct functioning of skeletal muscle.

The dystrophin protein is located in the plasma membrane of skeletal muscle, and is an integral part of the dystrophin-glycoprotein complex (DGC). The DGC forms a link between the sarcolemma (the muscle cell membrane) and the cytoskeleton thereby ensuring cell membrane stability and preventing damage during lengthening contractions of the muscle. Dysferlin on the other hand is known to play a critical role in calcium dependent membrane repair. A defect in either protein’s role has a detrimental effect on the muscle.

A new research article published this month in Skeletal Muscle uses dystrophin/dysferlin double knock-out (DKO) mice to look at how muscle pathology in dysferlin-null mice is exacerbated by an additional dystrophin deficiency. DKO mice show increased histopathology, decreased sarcolemmal integrity and severe functional defects. The double deficiency causes more severe muscular dystrophy than dysferlin-deficient or wild type mice, and also results in the mice being physically weaker, suffering from contraction-induced injuries and having a low force production. In addition, onset of the muscle pathology in mice lacking both dystrophin and dysferlin is earlier than in the dysferlin-deficient mice.

Han et al. reveal that the role dysferlin has in repairing damaged membranes can be unmasked by a dystrophin deficiency. In dystrophin deficient mice, the initial injury caused by lengthening muscle contractions is more severe than in wild type and dysferlin-null mice. Dystrophin deficient mice are however capable of recovery, revealing the presence of an active membrane repair process to restore membrane integrity. Dysferlin mice on the other hand show a poor recovery, as do DKO mice. These results suggest that the DKO mouse model may be useful in the development of therapies designed to treat dysferlinopathies – muscular dystrophies caused by a defect in the function of the dysferlin protein.

To keep up to date with the latest articles from Skeletal Muscle, why not visit our homepage and register to receive article alerts?

Read more]]> Skeletal Muscle, a new BioMed Central journal focused on mechanistic studies advancing the understanding of skeletal muscle biology, has now been accepted by the National Library of Medicine for appearance in PubMed, the free citation resource, located at the National Institutes of Health in the United States.

Cataloging on PubMed was the last step in the formal launching of the journal, which first appeared online in January of this year. The journal has received enthusiastic support from the community of scientists studying skeletal muscle. We hope that in the years to come Skeletal Muscle will be the first choice for high quality papers covering metabolic, developmental, structural and functional studies on this important tissue, under both normal and pathological conditions.