New drug on the blocks for athletes
Researchers at the European Molecular Biology Laboratory (EMBL), Italy, and Imperial College London, have now discovered a molecular signal that could help the body recover from a muscle-related injury. The study is published in the recent issue of the Journal of Cell Biology. The news is sure to interest those whose career depends upon being fit and there would be a considerable market if a drug made it to the market - especially when you consider that, as far as sport is concerned, money is often no object. One of the key players in regeneration following injury are muscle stem cells - so called satellite cells. A critical regulator of this process is calcineurin. It is activated by injury and controls the activity of other proteins involved in stem cell differentiation and the overall response to damage. Nadia Rosenthal, head of EMBL's Mouse Biology Unit, and her team have now found a naturally occurring version of calcineurin, called CnAß1 that is permanently active - it does not depend on whether the person is injured or not. When its gene is copied from DNA into RNA, certain pieces are cut out and therefore don't go on to form part of the protein product. This gene splicing explains why CnAß1 lacks a regulatory site that normally represses its activity. However, predictably, its expression is tightly regulated. "Permanently active CnAß1 is expressed only in proliferating stem cells and regenerating muscles, suggesting it as something like an ambulance man that is called only in response to muscle damage," explained Rosenthal. "This system allows flexible reaction to muscle injury." The study results To test the effects of permanent CnAß1 expression Enrique Lara-Pezzi from Rosenthal's lab overexpessed CnAß1 in muscle cells, and observed increased proliferation of muscle stem cells. Switching off the protein had the opposite effect; stem cells stopped dividing and differentiated into muscle cells instead. When CnAß1 was overexpressed in the muscles of transgenic mice, the animals were resistant to the destructive effects of muscle injury and regenerated the damage more efficiently. The scientists also uncovered how calcineurin accomplishes its effect on muscle. It blocks the action of FoxO, a transcription factor that induces genes involved in cell cycle repression and protein degradation. Suppressing the effects of FoxO, calcineurin ensures that proliferating cells stay alive and keep dividing to produce enough cells to repair muscle damage. However, it is not just athletes that could benefit from a drug targeting CnAß1. "Supplementary CnAß1 also reduces the formation of scars in damaged muscle, helps speed up the resolution of inflammation and protects muscle cells from atrophy [wasting] under starvation," said Rosenthal. "These effects make CnAß1 a promising candidate for new therapeutic approaches against muscle wasting." .
