Innovative Approach to Studying Mechanical Proteins and Their Role in Muscle Disorders

A research team at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), led by scientist Jorge Alegre-Cebollada, has pioneered a novel technique named TEVs-TTN to explore the mechanical functions of proteins by precisely controlling their cleavage. This process disables the proteins' ability to sense and transmit mechanical forces, providing new insights into muscular disease mechanisms. Published in ature Biomedical Engineering, this study demonstrates that disrupting the mechanical transmission of the protein titin can lead to muscular pathologies. Titin, the largest protein in animals, is fundamental to the structural integrity of sarcomeres, which are the contractile units of muscle cells. Mutations in the TTN gene are a primary cause of various muscular diseases and cardiomyopathies, as many mutations produce truncated titin proteins that impair muscle function.

The team used TEVs-TTN to deliberately cleave titin in muscle tissues, mimicking disruptions seen in patients with titin mutations. The resulting sarcomere disorganization was similar to pathological changes observed in affected individuals, including reduced cell volume, nuclear internalization, mitochondrial aggregation, and fibrosis. This controlled cleavage allowed researchers to analyze how mechanical failure at the molecular level affects muscle tissue, offering a new tool for testing potential therapies for these conditions.

Interestingly, the study found that complete disassembly of sarcomeres occurred within days following titin cleavage, yet muscle cells remained alive. This suggests that similar processes might be implicated in muscle tears, heart failure, or chemotherapy-related cardiotoxicity. The methodology marks a breakthrough in understanding how protein mechanics contribute to tissue and organ function. Other structural proteins such as dystrophin and integrins also play critical roles in cell stability and extracellular matrix interactions.

Overall, TEVs-TTN provides an invaluable platform for validating hypotheses about protein function and disease development. These findings could pave the way for innovative treatments targeting the mechanical aspects of muscle and organ diseases.

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