Immunometabolism of macrophages regulates skeletal muscle regeneration

Abstract

Sarcopenia is an age-related progressive loss of skeletal muscle mass, quality, and strength disease. In addition, sarcopenia is tightly correlated with age-associated pathologies, such as sarcopenic obesity and osteoporosis. Further understanding of disease mechanisms and the therapeutic strategies in muscle regeneration requires a deeper knowledge of the interaction of skeletal muscle and other cells in the muscle tissue. Skeletal muscle regeneration is a complex process that requires a series of highly coordinated events involving communication between muscle stem cells and niche cells, such as muscle fibro/adipogenic progenitors and macrophages. Macrophages play a critical role in tissue regeneration and the maintenance of muscle homeostasis by producing growth factors and cytokines that regulate muscle stem cells and myofibroblast activation. Furthermore, the aging-related immune dysregulation associated with the release of trophic factors and the polarization in macrophages transiently affect the inflammatory phase and impair muscle regeneration. In this review, we focus on the role and regulation of macrophages in skeletal muscle regeneration and homeostasis. The aim of this review is to highlight the important roles of macrophages as a therapeutic target in age-related sarcopenia and the increasing understanding of how macrophages are regulated will help to advance skeletal muscle regeneration.

Keywords: macrophages; metabolism; muscle regeneration; muscle stem cells; sarcopenia.

FIGURE 1

Skewed metabolic regulation and cytokine production in macrophages impairs skeletal muscle regeneration. Pro-inflammatory macrophages exhibit increased glucose uptake and glycolysis, leading to the accumulation of lactate and entry of glucose-derived pyruvate into the TCA cycle. Succinate accumulation in pro-inflammatory macrophages stabilizes HIF-1α, whereas anti-inflammatory macrophages increase the uptake of lipids and augment fatty acid oxidation. Pro-inflammatory macrophages are characterized by glycolytic metabolism, inducible nitric oxide synthase (iNOS) expression, and the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1α. Pro-inflammatory macrophages are critical in promoting myogenic precursor cells (MPCs) to enhance skeletal muscle regeneration. However, anti-inflammatory macrophages are the dominating type of macrophage in aged skeletal muscle; pro-inflammatory macrophages showed lower abundance in skeletal muscle and declined with age (Cui et al., 2019). Therefore, phenotypic and metabolic skewing may impair skeletal muscle regeneration in the elderly population.