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Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics (scRNA-Seq).

ABSTRACT: 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 two populations of skeletal muscle resident macrophages: TIM4- macrophages which are replenished from the blood and LYVE1+TIM4+ macrophages that locally self-renew (self-renewing resident macrophages, SRRMs). Using a CSF1R inhibition/withdrawal approach to specifically deplete SRRMs, we found that they provide a non-redundant 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, we showed that depletion of both resident populations through long term CSF1R inhibition changes muscle fiber composition from damage-sensitive glycolytic fibers towards damage-resistant glycolytic-oxidative fibers protecting muscle against contraction induced injury. This later finding reveals a new role for resident macrophages in modulating tissue metabolism and has therapeutic potential in light of the ongoing clinical testing of CSF1R inhibitors.

ORGANISM(S): Mus musculus

PROVIDER: GSE198055 | GEO | 2022/07/01

REPOSITORIES: GEO

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Project description:Background: Niemann-Pick disease type A (NPDA), a disease caused by mutations in acid sphingomyelinase (ASM), involves severe neurodegeneration and early death. Intracellular lipid accumulation and plasma membrane alterations are implicated in the pathology. ASM is also linked to the mechanism of plasma membrane repair, so we investigated the impact of ASM deficiency in skeletal muscle, a tissue that undergoes frequent cycles of injury and repair in vivo. Methods: Utilizing the NPDA/B mouse model ASM−/− and wild type (WT) littermates, we performed excitation- contraction coupling/Ca2+ mobilization and sarcolemma injury/repair assays with isolated flexor digitorum brevis fibers, proteomic analyses with quadriceps femoris, flexor digitorum brevis, and tibialis posterior muscle and in vivo tests of the contractile force (maximal isometric torque) of the quadriceps femoris muscle before and after eccentric contraction-induced muscle injury. Results: ASM−/− flexor digitorum brevis fibers showed impaired excitation-contraction coupling compared to WT, a defect expressed as reduced tetanic [Ca2+]i in response to electrical stimulation and early failure in sustaining [Ca2+]i during repeated tetanic contractions. When injured mechanically by needle passage, ASM−/− flexor digitorum brevis fibers showed susceptibility to injury similar to WT, but a reduced ability to reseal the sarcolemma. Proteomic analyses revealed changes in a small group of skeletal muscle proteins as a consequence of ASM deficiency, with downregulation of calsequestrin occurring in the three different muscles analyzed. In vivo, the loss in maximal isometric torque of WT quadriceps femoris was similar immediately after and 2 min after injury. The loss in ASM−/− mice immediately after injury was similar to WT, but was markedly larger at 2 min after injury. Conclusions: Skeletal muscle fibers from ASM−/− mice have an impairment in intracellular Ca2+ handling that results in reduced Ca2+ mobilization and a more rapid decline in peak Ca2+ transients during repeated contraction-relaxation cycles. Isolated fibers show reduced ability to repair damage to the sarcolemma, and this is associated with an exaggerated deficit in force during recovery from an in vivo eccentric contraction- induced muscle injury. Our findings uncover the possibility that skeletal muscle functional defects may play a role in the pathology of NPDA/B disease.

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Metabolic reprogramming of skeletal muscle by resident macrophages points to CSF1R inhibitors as muscular dystrophy therapeutics (scRNA-Seq).

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