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Muscle resident macrophages as a new target for muscular dystrophy treatment

New research with mice has revealed the role of muscle-resident macrophages in muscle regeneration therapy.

A new study, conducted at the Biomedical Research Centre at the University of Columbia, identified a population of self-renewing resident macrophage (SRRM) that cleared damaged-induced apoptotic cells early after muscle injury.  

The study, published in Science Translational Medicine, used a mouse model of Duchenne muscular dystrophy (DMD) to observe the effects of depleting resident macrophages via colony stimulating factor 1 receptor (CSF1R) inhibition on muscle fibre composition.  

DMD is a rare muscle disorder, but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. Although rarely affecting females, they are not completely excluded, and current treatments are limited to alleviating symptoms and managing the disease.  

The authors reported, “This work reveals a previously unidentified role for resident macrophages (RMs) in modulating tissue metabolism and may have therapeutic potential given the ongoing clinical testing of CSF1R inhibitors.” 

Identifying TIM4 as a SRRM surface marker  

In this study, infiltrating macrophages and RMs were purified, and their transcriptomes were compared to identify a potential distinguishing marker.  

Single-cell RNA sequencing revealed that Timd4 alone could be used to identify RMs throughout muscle regeneration. 

The absence of resident macrophages impairs muscle regeneration 

Although the importance of infiltrating macrophages in the regeneration of skeletal muscle is well established, the role of resident macrophages has yet to be characterised in detail, mainly due to the lack of a specific marker for their identification.  

CSFR1 signalling, which macrophages require for proliferation and survival, was inhibited to assess the importance of SRRMs in muscle regeneration. Histological analysis showed that CSF1R inhibitor treatment exhibited large number of unengulfed necrotic fibres and reduced a number of regenerating fibres.  

Therapeutic potential of CSF1R inhibitors  

Interestingly, the study then demonstrated that depletion of muscle RMs in DMD model mice protected dystrophic muscle against damage through metabolic reprogramming of muscle fibres.  

The researchers subjected treated and control DMD mice to a moderate-intensity downhill treadmill exercise to induce mild muscle damage. They found that CSF1R inhibition, for as short as 2 to 3 months, could protect dystrophic muscle against eccentric contraction-induced injury, as shown by reduced concentrations of circulating creatine kinase after exercise.  

Although seemingly paradoxical, the authors suggested a switch of muscle fibre-type from damage-sensitive glycolytic fibres toward damage-resistant glycolytic-oxidative fibres, accompanying CSF1R inhibition.  

RNA analysis also illustrated an upregulation of genes involved in pathways of muscle differentiation, fatty acid oxidation, and angiogenesis in CSF1R inhibited DMD muscle.  

These results suggest a metabolic change upon CSF1R inhibition and point towards the therapeutic potential of CSF1R inhibitors in muscular dystrophies. 

Written by Harry Yuen, Science Writer Intern

Image Credit: Canva