Flagship projects

Decoding the mechanical sensors of muscle to improve treatment of disease

IMPACT: understanding how mechanical stress disrupts muscle in neuromuscular diseases 

Stéphane Vassilopoulos, PhD

The IMPACT project investigates how key muscle structures called costameres respond to mechanical forces, and why their disruption progressively weakens muscle fibres in several neuromuscular diseases, in particular Duchenne muscular dystrophy and centronuclear myopathies.

Scientific challenge

Costameres allow muscle to transmit contractile forces while preserving its integrity. When they are disrupted, fibres become vulnerable and break down under repeated mechanical stress. Recent work has also shown that these structures relay mechanical signals all the way to the nucleus, influencing gene activity. Their dysfunction could therefore contribute directly to the progression of several diseases.

Key questions to unravel

The team aims to clarify how costameres control two proteins, YAP and TAZ, which act as mechanical sensors. In healthy muscle, they remain at the periphery of the cell; in some myopathies, they move to the nucleus and switch on inappropriate genes. The project sets out to understand this dysregulation and its consequences for the architecture and function of muscle, and to determine whether this pathway could become a therapeutic target shared by several diseases.

Scientific and methodological approach

The researchers will analyse muscle cells from patients and experimental models of Duchenne muscular dystrophy and centronuclear myopathies. They will study how costamere abnormalities alter the localisation and activity of YAP and TAZ, as well as the organisation of the nucleus and gene expression. The project draws on very high-resolution imaging technologies able to visualise muscle architecture at the nanometre scale, and on the evaluation of therapeutic strategies aimed at reducing abnormal YAP/TAZ activity.

We hope to identify new therapeutic targets and to show that molecules currently being developed in oncology can be repurposed to improve treatments for muscle diseases. This work could lead to new therapeutic approaches combining gene therapy with the modulation of mechanotransduction pathways, with potential applications well beyond muscle diseases.

Stéphane Vassilopoulos, co-team leader of a research team at the Institute’s Center of Research in Myology

Expected impact on research and clinical practice 

IMPACT could reveal a biological pathway shared by several muscle diseases and pave the way for treatments that complement gene therapy. Early observations suggest that some defects can be corrected by modulating YAP/TAZ. The imaging tools developed as part of this project will also be a valuable resource for the study of other neuromuscular diseases.