Targeting the SOD1‒MMP‐2‒COLXVII axis: A therapeutic strategy for age‐related tissue degeneration

Aging is marked by a decline in tissue integrity, particularly in skin and muscle, driven by oxidative stress and extracellular matrix (ECM) degradation. Superoxide dismutase 1 (SOD1) deficiency exacerbates these processes, accelerating atrophy. Matrix metalloproteinase‐2 (MMP‐2), a key enzyme in ECM breakdown, targets collagen type XVII (COLXVII), which is critical for tissue structure and stability. In this study, we investigated the role of MMP‐2 in SOD1 ‐deficient models and assessed the therapeutic potential of its inhibition. To assess the impact of MMP inhibition on wound healing and skin atrophy, we applied batimastat, a broad‐spectrum MMP inhibitor, to Sod1‐deficient mice. While batimastat inhibits multiple MMPs, including MMP‐2, MMP‐9, and MMP‐14, its application allows us to evaluate the general role of MMP activity in SOD1‐related ECM degradation and repair processes. Using Sod1/Mmp2 double‐knockout mice and the MMP inhibitor batimastat, we observed that MMP‐2 deletion restored skin thickness, increased COLXVII expression, and improved wound healing. Batimastat application yielded similar benefits, reversing skin atrophy and enhancing repair. In muscle tissue, MMP‐2 inhibition restored muscle mass and function, with parallel improvements in SOD1 mutant Caenorhabditis elegans . Preservation of COLXVII emerged as a critical mechanism, significantly mitigating SOD1‐related tissue degeneration. These findings highlight MMP‐2's pivotal role in senescence‐associated tissue atrophy and underscore the therapeutic potential of targeting the SOD1‒MMP‐2‒COLXVII axis to combat age‐related tissue degeneration.