Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet, the contribution of immune dysfunction to regenerative failure is unknown. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator MANF is induced following muscle injury in young mice, but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in the aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring the myeloid response through immune modulation is a promising therapeutic strategy to improve the regenerative capacity of aged muscles.

Age-related decline in skeletal muscle regenerative capacity is multifactorial, yet, the contribution of immune dysfunction to regenerative failure is unknown. Here, we uncover a new mechanism of immune modulation operating during skeletal muscle regeneration that is disrupted in aged animals and relies on the regulation of macrophage function. The immune modulator MANF is induced following muscle injury in young mice, but not in aged animals, and its expression is essential for regenerative success. Regenerative impairments in the aged muscle are associated with defects in the repair-associated myeloid response similar to those found in MANF-deficient models and could be improved through MANF delivery. We propose that restoring the myeloid response through immune modulation is a promising therapeutic strategy to improve the regenerative capacity of aged muscles.