Cell death, clearance and immunity in the skeletal muscle

The skeletal muscle is an immunologically unique tissue. Leukocytes, virtually absent in physiological conditions, are quickly recruited into the tissue upon injury and persist during regeneration. Apoptosis, necrosis and autophagy coexist in the injured/regenerating muscles, including those of patients with neuromuscular disorders, such as inflammatory myopathies, dystrophies, metabolic and mitochondrial myopathies and drug-induced myopathies. Macrophages are able to alter their function in response to microenvironment conditions and as a consequence coordinate changes within the tissue from the early injury throughout regeneration and eventual healing, and regulate the activation and the function of stem cells. Early after injury, classically activated macrophages ('M1') dominate the picture. Alternatively activated M2 macrophages predominate during resolution phases and regulate the termination of the inflammatory responses. The dynamic M1/M2 transition is increasingly felt to be the key to the homeostasis of the muscle. Recognition and clearance of debris originating from damaged myofibers and from dying stem/progenitor cells, stromal cells and leukocytes are fundamental actions of macrophages. Clearance of apoptotic cells and M1/M2 transition are causally connected and represent limiting steps for muscle healing. The accumulation of apoptotic cells, which reflects their defective clearance, has been demonstrated in various tissues to prompt autoimmunity against intracellular autoantigens. In the muscle, in the presence of type I interferon, apoptotic myoblasts indeed cause the production of autoantibodies, lymphocyte infiltration and continuous cycles of muscle injury and regeneration, mimicking human inflammatory myopathies. The clearance of apoptotic cells thus modulates the homeostatic response of the skeletal muscle to injury. Conversely, defects in the process may have deleterious local effects, guiding maladaptive tissue remodeling with collagen and fat accumulation and promoting autoimmunity itself. There is strong promise for novel treatments based on new knowledge of cell death, clearance and immunity in the muscle.