Mechanosensitive Calcium Dysregulation in Aged Tenocytes Narrows the Anabolic Window and Drives Senescence
Tendinopathy is a highly prevalent and disabling musculoskeletal disorder whose incidence and severity increase markedly with ageing. Despite its strong mechanical etiology, current treatments remain largely palliative, reflecting an incomplete understanding of how ageing alters tendon mechanobiology at the cellular level. Tendon degeneration is characterized by persistent inflammation, dysregulated extracellular matrix (ECM) remodelling, and impaired regeneration, suggesting that age-associated cellular changes fundamentally compromise adaptive mechanosensitive signalling in tenocytes.Mechanotransduction in tendon is critically dependent on Calcium signalling, which enables tenocytes to translate mechanical cues into coordinated transcriptional and metabolic responses. The mechanosensitive ion channel PIEZO1 has emerged as a dominant regulator of tendon Calcium influx and load adaptation. However, how PIEZO1-dependent Calcium signalling is altered during ageing - and how these changes are integrated with intracellular metabolic processes - remains unknown. In parallel, cellular senescence progressively accumulates in ageing and injured tendons and is causally linked to chronic inflammation, ECM degradation, and impaired repair. Senescence is tightly associated with mitochondrial dysfunction, yet the impact of senescence-associated mitochondrial impairment on mechanosensitive Calcium signalling in tenocytes has not been mechanistically addressed.