Pan-tissue scaling of stiffness versus fibrillar collagen reflects contractile-strain-driven collagen degradation

Polymer network properties such as stiffness often exhibit characteristic power laws in polymer density and other parameters. However, it remains unclear whether diverse animal tissues, composed of many distinct polymers, exhibit such scaling and how cell and molecular mechanisms contribute towards homeostatic differences among tissues. Here, we examined many diverse tissues from adult mouse and embryonic chick to determine if stiffness (Etissue) follows a power law in relation to the most abundant animal protein, collagen-I, even with molecular perturbations. We quantified fibrillar collagen in intact tissue by label-free second harmonic generation (SHG) imaging and from tissue extracts by mass spectrometry (MS), and collagenase-mediated decreases were also tracked. Pan-tissue power laws for tissue stiffness versus collagen-I levels measured by SHG or MS exhibit sub-linear scaling that aligns with results from cellularized gels of collagen-I but not acellular gels. Inhibition of cellular myosin-II based contractile strains fits the scaling, and combination with inhibitors of matrix metalloproteinases (MMPs) show collagenase activity is strain - not stress- suppressed in tissues, consistent with past studies of gels and fibrils. Beating embryonic hearts and tendons, which differ in both collagen levels and stiffness by >1,000-fold, similarly suppressed collagenases at physiological strains of ≈5%, with fiber-orientation regulating degradation via strain-dependent collagen molecular conformation. Scaling of Etissue based on “use-it-or-lose-it” kinetics provides insight into scaling of organ size, microgravity effects, and regeneration processes while suggesting contractility-driven therapeutics.