Recombinant humanized collagen ameliorates ischemic myopathy through limiting natural IgM-mediated lectin complement activation

Abstract

Despite technological advances in endovascular procedures, therapeutics that provide supportive microenvironments to repair ischemic muscles are limited for the treatment of advanced lower extremity peripheral artery disease (PAD). Here, based on the two major extracellular matrix components in skeletal muscle, the efficacies of recombinant humanized collagen type I and III (rhCol I and rhCol III) in regenerating tibialis anterior muscle after hindlimb ischemia were studied. Repeated intramuscular injections of rhCol I or rhCol III preserved myofiber structure and accelerated myofiber regeneration within one-week after injury. Proteomic signature demonstrated a reduced lectin complement activation in the rhCol I- and III-treated muscles. We identified a competitive binding between rhCol and natural IgM (nIgM), which inhibits nIgM-mediated lectin complement activation, as the underlying mechanism contributing to a protective microenvironment after ischemic injury. Furthermore, the complement-inhibiting rhCol I and rhCol III treatments exhibit long-term protection for ischemic muscle with ameliorated muscle pathology and improved muscle function. Our findings provide a promising biomaterial-based approach for treating ischemic myopathy induced by PAD.