Discovery of molecular signal that helps muscle regenerate and protects it from atrophy

It does not take much to injure a muscle. Sometimes one sudden, inconsiderate movement does the job.

Unfortunately, damaged muscles are not as efficient at repair as other tissues such as bone. Researchers of the European Molecular Biology Laboratory's Mouse Biology Unit (EMBL), Italy, and the Harefield Heart Science Centre of Imperial College London, have now discovered a molecular signal that helps muscle regenerate and protects it from atrophy. In this week's issue of the Journal of Cell Biology they report that the naturally occurring protein is a promising candidate for new strategies in treating muscle damage and wasting.

Muscle regeneration after injury is complex and requires a coordinated interplay between many different processes. Key players in regeneration are muscle stem cells, so-called satellite cells. They divide and produce many new muscle cells to fix the damage incurred by injury. A crucial regulator of muscle function and repair is a signalling molecule called calcineurin. It is activated by injury and controls the activity of other key proteins involved in differentiation and the 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 and uncouples the protein's activity from injury signals. The expression of CnAß1, however, is tightly regulated. It is expressed from the same gene as other versions of the calcineurin Aß subunit that are not permanently active. CnAß1 gains its unique properties by a process called RNA splicing. When the gene has been copied from DNA into RNA certain pieces of information are cut out of the RNA molecule and will not make part of the protein. This is why CnAß1 lacks a regulatory site that normally represses its activity.

“This system allows flexible reaction to muscle injury,” says Rosenthal. “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.”

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.

Using sophisticated molecular techniques the scientists revealed that calcineurin accomplishes its effect on muscle by inhibiting another protein called FoxO. FoxO is a transcription factor, a protein that plays a crucial role in skeletal muscle atrophy through the induction of 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.

“Supplementary CnAß1 also reduces the formation of scars in damaged muscle, helps speed up the resolution of inflammation and protects muscle cells from atrophy under starvation,” says Rosenthal. “These effects make CnAß1 a promising candidate for new therapeutic approaches against muscle wasting.”