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The internal clock of our cells is influenced by mechanical forces

Understanding how aging and certain associated diseases such as certain types of cancer work is one of the major current challenges in science. Now, researchers from IBEC, based at the Barcelona Science Park, have taken a step further in this knowledge by demonstrating how physical forces disrupt the circadian clock of cells, the mechanism that controls physiological changes every 24 hours. This finding can help better understand this interaction, as the circadian clock stops functioning properly with aging and certain diseases.

Living organisms possess an internal biological cycle known as the circadian clock, which regulates fundamental physiological activities such as metabolism, hormonal variations, body temperature, and blood pressure fluctuations.

The proper functioning of the clock is crucial for living beings to anticipate changes between day and night and adapt their physiology accordingly. The classic example of a misalignment of this clock with evident physiological effects is the well-known jet lag that occurs when we cross different time zones by airplane.

A group of researchers led by the ICREA Research Professor and leader of the Integrative Cell and Tissue Dynamics group at IBEC, Xavier Trepat, has taken a further step in deciphering it’s functioning by describing the mechanism through which the circadian clock of cells becomes deregulated in response to external physical forces. The research, recently published in the Journal of Cell Biology, is the result of a collaboration between IBEC and Pompeu Fabra University in Barcelona.

YAP protein: key in the deregulation of the internal clock in response to physical forces

In mammals, the central circadian clock is situated in the brain and primarily regulated by light. However, each cell possesses its own individual internal clock, which senses and adjusts to the microenvironment.

By conducting in vitro experiments using mouse fibroblasts, which are connective tissue cells responsible for maintaining structural integrity, the researchers have observed that the dysregulation of the circadian clock is linked to the YAP protein (Yes-Associated Protein). Interestingly, this protein also governs cell proliferation and has implications in the development of metastases across various types of cancer.

The YAP protein serves as the convergence point for external mechanical signals, enabling cells to sense the rigidity of their environment. Initially present in an inactive form within the cytoplasm of cells, YAP becomes activated in response to mechanical stimuli. Once activated, it translocates to the nucleus, where it selectively influences specific “target” genes, initiating a response to the initial stimulus.

Researchers have utilized advanced techniques such as confocal microscopy, microfabrication, and customized computer analysis to investigate the functionality of the circadian clock at the cellular level. By applying controlled mechanical, biochemical, and genetic perturbations to cells, they have discovered that one of the “target” genes influenced by YAP is Rev-erbα, a central gene involved in circadian clock regulation.

The finding that YAP alters cellular rhythm adds a new dimension to circadian clock regulation. It provides elements that can help explain the dysfunction of the clock in cancer cells and during the aging process.

Xavier Trepat, leader of the study, is also a professor at the Universitat de Barcelona (UB) and member of the Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN).

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