Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics

The role of tissue-resident macrophages during tissue regeneration or fibrosis is not well understood, mainly due to the lack of a specific marker for their identification. Here, we identified three populations of skeletal muscle-resident myelomonocytic cells: a population of macrophages positive for lymphatic vessel endothelial receptor 1 (LYVE1) and T cell membrane protein 4 (TIM4 or TIMD4), a population of LYVE1^-TIM4^- macrophages, and a population of cells likely representing dendritic cells that were positive for CD11C and major histocompatibility complex class II (MHCII). Using a combination of parabiosis and lineage-tracing experiments, we found that, at steady state, TIM4^- macrophages were replenished from the blood, whereas TIM4⁺ macrophages locally self-renewed [self-renewing resident macrophages (SRRMs)]. We further showed that Timd4 could be reliably used to distinguish SRRMs from damage-induced infiltrating macrophages. Using a colony-stimulating factor 1 receptor (CSF1R) inhibition/withdrawal approach to specifically deplete SRRMs, we found that SRRMs provided a nonredundant function in clearing damage-induced apoptotic cells early after extensive acute injury. In contrast, in chronic mild injury as seen in a mouse model of Duchenne muscular dystrophy, depletion of both TIM4^-- and TIM4⁺-resident macrophage populations through long-term CSF1R inhibition changed muscle fiber composition from damage-sensitive glycolytic fibers toward damage-resistant glycolytic-oxidative fibers, thereby protecting muscle against contraction-induced injury both ex vivo and in vivo. This work reveals a previously unidentified role for resident macrophages in modulating tissue metabolism and may have therapeutic potential given the ongoing clinical testing of CSF1R inhibitors.