The myofascial rheostat: hyaluronan molecular weight dynamics and purinergic signalling as a physiological feedback system

Fascia, the connective tissue network enveloping muscles, organs, and viscera, functions as a hyaluronan (HA)-rich adaptive interface that senses and responds to inflammatory cues. This narrative review synthesizes ECM literature across niches to examine the calcium-hyaluronan (CHA) axis, a feedback loop linking Ca² + signaling to HA synthesis via HAS2 and molecular weight–dependent signaling through CD44 and RHAMM receptors. We propose that the CHA axis is constrained further by ATP/NAD + -mediated feedback and functions as a rheostat regulated by four distinct constraint types (1): Mechanical loading and shear regulate HA turnover, hydration, and viscosity via YAP/TAZ and integrin mechanosensing (2). Inflammatory cytokines drive HAS2/HA accumulation during chronic irritation or injury through CD44/RHAMM signaling (3). Metabolic energy availability provides purinergic brakes via AMPK/SIRT1 that suppress synthesis when ATP is scarce (4). HA clearance mechanisms—hyaluronidases, TMEM2/CEMIP, lymphatic drainage, and interstitial fluid flow—which may be as critical as synthesis itself. This is the first review integrating the domains of research across cell types, with clinical relevance in cancer and wound healing as well as exercise physiology and longevity protocols.