Background
The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address.

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Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments

The apoptotic event of phosphatidylserine exposure and its recognition by the receptor BAI1 has an unexpected new role as a signal enhancing mouse myoblast fusion, an insight with relevance to some congenital muscle diseases and muscle injury treatments. Apoptotic cell death occurs throughout development and homeostasis in healthy tissues, including skeletal muscle. This study questions previous assumptions that the resulting dead cells have no beneficial effects. Kodi Ravichandran and colleagues show that during skeletal muscle differentiation in mice, a fraction of precursor muscle cells undergoes apoptosis, and that these cells provide a key signal — phosphatidylserine — that promotes muscle development. The idea that the body may use cell death not only to rid itself of unwanted cells, but also to regulate differentiation adds an intriguing dimension to cell turnover within tissues. Skeletal muscle arises from the fusion of precursor myoblasts into multinucleated myofibres1,2. Although conserved transcription factors and signalling proteins involved in myogenesis have been identified, upstream regulators are less well understood. Here we report an unexpected discovery that the membrane protein BAI1, previously linked to recognition of apoptotic cells by phagocytes3, promotes myoblast fusion. Endogenous BAI1 expression increased during myoblast fusion, and BAI1 overexpression enhanced myoblast fusion by means of signalling through ELMO/Dock180/Rac1 proteins4. During myoblast fusion, a fraction of myoblasts within the population underwent apoptosis and exposed phosphatidylserine, an established ligand for BAI1 (ref. 3). Blocking apoptosis potently impaired myoblast fusion, and adding back apoptotic myoblasts restored fusion. Furthermore, primary human myoblasts could be induced to form myotubes by adding apoptotic myoblasts, even under normal growth conditions. Mechanistically, apoptotic cells did not directly fuse with the healthy myoblasts, rather the apoptotic cells induced a contact-dependent signalling with neighbours to promote fusion among the healthy myoblasts. In vivo, myofibres from Bai1−/− mice are smaller than those from wild-type littermates. Muscle regeneration after injury was also impaired in Bai1−/− mice, highlighting a role for BAI1 in mammalian myogenesis. Collectively, these data identify apoptotic cells as a new type of cue that induces signalling via the phosphatidylserine receptor BAI1 to promote fusion of healthy myoblasts, with important implications for muscle development and repair.

/pdf/phosphatidylserine-receptor-bai1-and-apoptotic-cells-as-new-1dvjymkxnz.pdf

Phosphatidylserine receptor BAI1 and apoptotic cells as new promoters of myoblast fusion.

Injury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle

http://www.treat-nmd.eu/downloads/file/dmd/Willmann_Mammalian-animal-models-for-Duchenne-muscular-dystrophy_2009.pdf

Mammalian animal models for Duchenne muscular dystrophy

Taurine is a natural amino acid present as free form in many mammalian tissues and in particular in skeletal muscle. Taurine exerts many physiological functions, including membrane stabilization, osmoregulation and cytoprotective effects, antioxidant and anti-inflammatory actions as well as modulation of intracellular calcium concentration and ion channel function. In addition taurine may control muscle metabolism and gene expression, through yet unclear mechanisms. This review summarizes the effects of taurine on specific muscle targets and pathways as well as its therapeutic potential to restore skeletal muscle function and performance in various pathological conditions. Evidences support the link between alteration of intracellular taurine level in skeletal muscle and different pathophysiological conditions, such as disuse-induced muscle atrophy, muscular dystrophy and/or senescence, reinforcing the interest towards its exogenous supplementation. In addition, taurine treatment can be beneficial to reduce sarcolemmal hyper-excitability in myotonia-related syndromes. Although further studies are necessary to fill the gaps between animals and humans, the benefit of the amino acid appears to be due to its multiple actions on cellular functions while toxicity seems relatively low. Human clinical trials using taurine in various pathologies such as diabetes, cardiovascular and neurological disorders have been performed and may represent a guide-line for designing specific studies in patients of neuromuscular diseases.

/pdf/taurine-the-appeal-of-a-safe-amino-acid-for-skeletal-muscle-jr4e440cl0.pdf

Annarnaria De Luca

Papers

Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy