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Skeletal muscle, which accounts for over 40% of the total mass in healthy individuals, plays a central role in maintenance of organismal homeostasis. Conversely, muscle atrophy upon acute and chronic conditions, ranging from genetic muscular dystrophy to critical illnesses, cachexia and sarcopenia, significantly correlates with levels of disability and is an important predictor of mortality. Despite the urgent medical need, treatments able to efficiently counteract muscle loss are lacking due to an incomplete understanding of the underlying intricate molecular mechanisms of regulation.

In this work a team led by Carlo Rinaldi elucidated a critical molecular mechanism of muscle homeostasis, where Androgen Receptor (AR) cooperates to orchestrate a muscle hypertrophy programme, forming a transcriptional complex with SMAD4 in response to conditions of increased demand, such as physical exercise, denervation, and cachexia. They discovered that in spinal and bulbar muscular atrophy (SBMA), a genetic neuromuscular disease caused by a polyglutamine expansion (polyQ) in AR, this cooperative ability is lost, resulting in the severe primary muscle weakness and atrophy observed in affected individuals. 

The researches went on showing that activation of the BMP-SMAD4 axis is sufficient to overcome this polyQ AR defective capability and restores the neuromuscular phenotype in a proof-of-concept preclinical study in transgenic mice, overall supporting the development of treatments able to fine-tune AR-SMAD4 transcriptional cooperativity as a promising target for SBMA and other conditions associated with muscle loss.

While uncovering a critical mechanism of the anabolic effect on skeletal muscle of androgens and androgen-related molecules -the most widely used doping agents, this study also provides the molecular explanation of why men have (usually!) more muscle mass than women. 

Link to the paper

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