Durable Muscle Extracellular Matrix Engineered with Adhesive Phenolic Moieties for Effective Skeletal Muscle Regeneration in Muscle Atrophy

Abstract

Muscle atrophy detrimentally impacts health and exacerbates physical disability, leading to increased mortality. In particular, sarcopenia, aging-related degenerative muscle loss, necessitates urgent remedies. Current approaches for treating muscle atrophy include exercise and nutrition, while drug exploration remains in its early stages. Cell therapy, focusing on satellite cells, faces significant challenge due to poor engraftment, safety issue, and high cost. Cell-free approach using extracellular matrix (ECM) shows a regenerative potential, but a lack of mechanical and adhesive properties hinders prolonged efficacy of ECM therapy. Here, durable muscle ECM (MEM) hydrogels for muscle atrophy by fortifying MEM with adhesive phenolic moieties including catechol and pyrogallol are demonstrated. The resultant phenolic MEM hydrogels exhibit enhanced mechanical and adhesive properties and provide sustained muscle-like microenvironments to address muscle atrophy. No local and systemic toxicities are observed after phenolic MEM injection into tibialis anterior muscle. Notably, these engineered MEM hydrogels, devoid of cells or drugs, induce tissue rejuvenation by promoting muscle protein synthesis and facilitating functional muscle recovery in mouse models of disuse- and age-induced atrophy. This study introduces cell-free, ECM-based therapeutics with translational potential for muscle atrophy by reversing muscle loss and restoring function. Phenolic adhesive muscle extracellular matrix hydrogels with improved tissue adhesion, mechanical properties, and muscle-specific cues are developed to treat muscle loss. These hydrogels facilitate muscle regeneration in disuse-induced muscle atrophy and sarcopenia mouse models by generating enduring muscle-like microenvironments for rejuvenating effect without the use of stem cells or drugs. The engineered hydrogels can advance therapeutic strategies for muscle atrophy. image