Macrophage-derived glutamine boosts satellite cells and muscle regeneration

Abstract

Muscle regeneration is sustained by infiltrating macrophages and consequent satellite cell (SC) activation 1 – 4 . Macrophages and SC communicate in different ways 1 – 5 but their metabolic interplay was never investigated so far. Here, we found that muscle injuries and aging are characterized by intratissutal glutamine restriction. Low glutamine levels endow macrophages with the metabolic ability to secrete glutamine via enhanced glutamine synthetase (GS) activity at the expense of glutamate dehydrogenase-1 (GLUD1)-mediated glutamine oxidation. Glud1 knockout (KO) macrophages display constitutively high GS activity which prevents glutamine shortage. Import of macrophage-derived glutamine by SC through the glutamine-transporter SLC1A5 activates mTOR and promotes SC proliferation and differentiation. Consequently, macrophage-specific deletion or pharmacological inhibition of GLUD1 improves muscle regeneration and functional recovery in response to acute injury, ischemia, or aging. Conversely, SLC1A5 blockade in SC or GS inactivation in macrophages negatively affects SC functions and muscle regeneration. These results highlight a metabolic cross-talk between SC and macrophages whereby macrophage-derived glutamine sustains SC functions. Thus, GLUD1 targeting offers new therapeutic opportunities for the regeneration of injured or aged muscles.

Delineating the relationship between immune system aging and myogenesis in muscle repair

“…It was also recently shown that macrophages can sense and respond to metabolites produced in muscle. Shang et al demonstrated that age‐ and injury‐related decreases in glutamine are compensated for by macrophages, which produce glutamine that is taken up by satellite cells, facilitating their proliferation and differentiation (Shang et al., 2020).…”

A Pound of Flesh: What Cachexia Is and What It Is Not

“…Sarcopenia is characterized by a chronic deficit in muscle protein storage, which results in the progressive loss of muscle mass quality and strength and/or physical performance [ 1 , 26 , 27 , 28 ]. So far, two distinct forms of sarcopenia have been described: age-mediated loss of muscle mass (primary sarcopenia) and loss of muscle mass without the emphasis on muscle function (secondary sarcopenia or disease-related sarcopenia), which can be associated, among others, with COPD, heart, and renal failure [ 29 ].…”

“…So far, two distinct forms of sarcopenia have been described: age-mediated loss of muscle mass (primary sarcopenia) and loss of muscle mass without the emphasis on muscle function (secondary sarcopenia or disease-related sarcopenia), which can be associated, among others, with COPD, heart, and renal failure [ 29 ]. Although sarcopenia is typically observed in the elderly [ 27 , 28 , 30 ], it can be a severe comorbidity of cancer (secondary sarcopenia), malnutrition, and disuse conditions in young subjects [ 1 ]. Nevertheless, most sarcopenic individuals are not cachectic.…”

Immunometabolism of Tissue-Resident Macrophages – An Appraisal of the Current Knowledge and Cutting-Edge Methods and Technologies

“…In the first study, Berardi, Mazzone, and colleagues elucidate a system of muscle regeneration by which muscle TRMs act as sensors of glutamine availability which is a key determinant of successful regeneration. Specifically, upon muscle injury or in aged muscle, glutamine levels fall in the extracellular milieu, inducing TRMs to switch from glutamate oxidation (via glutamate dehydrogenase 1, GLUD1) to increased glutamine synthesis (via glutamine synthetase, GS) and release (155). Satellite cells, the multipotent muscle stem cell, consume TRM-derived glutamine via the transporter SLC1A5 which facilitates their proliferation and differentiation into mature muscle.…”

“…Satellite cells, the multipotent muscle stem cell, consume TRM-derived glutamine via the transporter SLC1A5 which facilitates their proliferation and differentiation into mature muscle. This circuit was tunable, allowing for both improved and impaired muscle regeneration across multiple in vivo models (155). In the second study, Nave, Saher, and colleagues report that microgliamediated CNS repair depends on the synthesis of desmosterol (instead of the sterol synthesis end-product cholesterol) from the engulfed myelin (156).…”