The growing obesity epidemic is currently an expanding threat to global health. Obesity-related metabolic dysfunction is a risk factor for long-term cardiovascular complications, which highlights the major impact of obesity on population health. Overnutrition, especially physical inactivity, is a major contributor to the development of obesity and diabetes. Consequently, physiologic interventions such as caloric restriction and exercise training have been shown to play various beneficial roles in the prevention and treatment of metabolic disorders.
Despite these insights, the understanding of the benefits of exercise remains limited. In particular, the molecular links between muscle function, the regulation of local immune responses, and exercise are currently largely unclear. This knowledge gap relates to the impact of localized muscle immune regulation and its interaction with muscle integrity, function and regeneration. Thus, dissecting muscle-specific immune regulation, as well as muscle function, adaptation, and regeneration, is critical for future advances in immunomodulation for small context-specific targeted interventions.
Recently, researchers from Helmholtz National Research Center, Germany, published an article entitled "Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration" in Cell Metab. In the journal Cell Metab., researchers at the National Research Center in Łódź published an article titled "Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration", in which they showed that IL6Ra TKO mice have significant impairments in muscle regeneration, and that the acquisition of Treg function restores impaired muscle repair in IL6Ra TKO mice.
From an immunological perspective, investigators have recently identified a specific population of tissue-regulatory T cells (Tregs) in skeletal muscle that display distinct T cell receptor (TCR) pools and specific transcriptomes.Tregs are characterized by the expression of CD4, CD25, and the transcription factor Foxp3, which is a major regulator of Treg development and function. In contrast to Tregs in lymphoid tissues, Tregs in non-lymphoid tissues (e.g., muscle) play a key role in the control and maintenance of tissue homeostasis, integrity, and function. Muscle Tregs have high expression levels of two regulatory proteins (Areg), members of the epidermal growth factor family, whose receptor (epidermal growth factor receptor EGFR) is expressed on immune cells and satellite cells (SCs) within the muscle. areg has recently been shown to play a central role in orchestrating mechanisms of host resistance and tolerance.
Here, researchers found that exercise promoted the stable induction of highly functional muscle-secreted Tregs while increasing the expression of two regulatory proteins (Areg), EGFR and ST2. Mechanistically, the investigators found that muscle Treg function as well as satellite and fiber-forming lipid progenitors required for muscle regeneration were significantly reduced in mice with T cells (TKO) deficient in IL6Ra. Using exercise and oligomyelitis models, IL6Ra TKO mice exhibited defective Tregs, functional maturation, and a more pronounced decrease in muscle mass. The muscle injury model demonstrated that IL6Ra TKO mice were significantly impaired in muscle regeneration.Acquisition of Treg function restored impaired muscle repair in IL6Ra TKO mice.
Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration
Image from source: https://doi.org/10.1016/j.cmet.2023.08.010
In summary, IL6Ra expression on T cells is the molecular interface that mediates Treg control of muscle function, adaptation and repair. The presented findings are clinically relevant given the correlation between anti-IL6R treatment and the development of myasthenia gravis.Functional specialization of Tregs in non-lymphoid tissues ensures the optimization of future application strategies, which will allow small context and/or environment-specific targeting of these relevant immune cells.
