Regulation of muscle growth and regeneration by the immune system

Key Points

  • Changes in the stages of myogenesis during muscle regeneration following injury coincide with changes in the phenotype and activation state of leukocytes that invade the damaged, regenerating tissue.

  • Macrophages dominate the inflammatory infiltrate in regenerating muscle, and they are biased towards an M1 phenotype during the early, proliferative stages of muscle regeneration and towards an M2 phenotype during the differentiation and growth phase of regeneration.

  • Signalling initiated by tumour necrosis factor (TNF), interferon-γ (IFNγ), interleukin-10 (IL-10) and insulin-like growth factor 1 (IGF1) has key roles in controlling the normal inflammatory response and myogenic response to muscle damage that is required to achieve muscle regeneration.

  • Disruptions of normal regulatory interactions between myeloid cells and muscle with regulatory T (Treg) cells, CD8+ T cells and fibro-adipogenic progenitor (FAP) cells can prevent successful muscle regeneration following acute injury.

  • Chronic muscle disease and muscle ageing disrupt the normal function of myeloid cells, FAP cells and Treg cells, which can lead to impaired muscle regeneration and increased muscle fibrosis.

  • Manipulations of myeloid cell phenotypes can improve muscle regeneration and growth following muscle trauma.

Abstract

Diseases of muscle that are caused by pathological interactions between muscle and the immune system are devastating, but rare. However, muscle injuries that involve trauma and regeneration are fairly common, and inflammation is a clear feature of the regenerative process. Investigations of the inflammatory response to muscle injury have now revealed that the apparently nonspecific inflammatory response to trauma is actually a complex and coordinated interaction between muscle and the immune system that determines the success or failure of tissue regeneration.

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Figure 1: Myogenic precursor cells proceed through a tightly regulated sequence of myogenic-regulatory gene expression during muscle regeneration.
Figure 2: Myogenesis during muscle regeneration is temporally linked with a transition from the initial inflammatory response to a type 2 immune response.
Figure 3: Pro-inflammatory cytokines link inflammation with muscle regeneration.
Figure 4: Interactions between myeloid cells, lymphoid cells, fibro-adipogenic progenitor cells and myogenic precursor cells determine the course of muscle growth and regeneration.
Figure 5: Dysregulation of the immune response to muscle injury increases muscle damage and fibrosis.

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Acknowledgements

The author is supported by National Institutes of Health grants 1RO1AR066036, 1RO1AG041147, 1RO1AR062579 and 1R21AR066817. The author apologizes to scientists whose work was not included in this Review because of limitations on the length of the Review.

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Correspondence to James G. Tidball.

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Glossary

Satellite cells

A population of muscle stem cells that are committed to the myogenic lineage and normally reside in a quiescent state at the surface of fully differentiated muscle fibres. They can be activated by muscle injury, leading them to proliferate and then either return to quiescence, fuse with existing muscle fibres or continue to differentiate to form new muscle fibres.

Myotubes

During muscle development and regeneration, postmitotic, mononucleated muscle cells fuse with neighbouring postmitotic muscle cells to form long, cylindrical, multinucleated myotubes. Eventually myotubes can grow to include hundreds of muscle nuclei, and they then undergo terminal differentiation to become mature muscle fibres.

mdx mice

Mutant mice that lack dystrophin, the deficient gene product in Duchenne muscular dystrophy (DMD), which is a progressive, lethal, muscle-wasting disease in humans. Both mdx dystrophy and DMD involve an early, acute onset of muscle damage and inflammation. However, subsequent DMD pathology is more severe than mdx pathology, in which there is an extensive period of remission following initial onset.

Macrophage memory

Cells of the innate immune system, including macrophages, can show changes in their response to immune challenges according to the conditions under which they differentiated or were previously activated. This 'trained' immunity or memory reflects epigenetic changes that influence signalling or metabolic pathways.

Fibro-adipogenic progenitor cells

(FAP cells). A population of muscle-resident mesenchymal cells that are lineage-negative, lack expression of integrin α7 and express CD34 and stem cell antigen 1, and that have the ability to differentiate into fibroblasts or adipocytes. Following acute injury, FAP cells can release factors that increase muscle cell differentiation and that promote repair.

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Tidball, J. Regulation of muscle growth and regeneration by the immune system. Nat Rev Immunol 17, 165–178 (2017). https://doi.org/10.1038/nri.2016.150

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