To What Degree Does Loss of Skeletal Muscle with Age Contribute to Immunosenescence?

Sarcopenia, the progressive loss of muscle mass and strength, is characteristic of aging. A perhaps surprisingly large fraction of the losses can be averted by strength training, but there are nonetheless inexorable processes of aging that, until therapies exist to repair this damage, will cause decline in muscle tissue over time even for those who maintain their fitness as best as possible. Researchers here consider the evidence for skeletal muscle tissue to do more than just move us around, but also to be an active participant in many aspects of metabolism. The focus in this open access paper is on the immune system: to what degree does sarcopenia contribute to the loss of immune function that also occurs with age?

In the last two decades, the perception of skeletal muscle as a pure locomotors unit has shifted. Muscle is increasingly recognized as an organ with immune regulatory properties. As such, skeletal muscle cells modulate immune function by signalling through different soluble factors, cell surface molecules, or cell-to-cell interactions. Although our knowledge of the muscle-immune system interplay has advanced considerably, the impact of age is relatively unknown. Sarcopenia may severely disturb this interaction, providing a potential explanation for the observed clinical outcomes of sarcopenic patients

Muscle is increasingly recognized as an endocrine organ producing and releasing cytokines and other peptides, which exert autocrine, paracrine, and endocrine activity on numerous tissues. Consequently, these soluble factors are commonly termed myokines. Proteomic profiling has been applied to the secretome of skeletal muscle and identified more than 300 potential myokines. Myokines such as IL-6, IL-7, IL-15, or LIF have been shown to modulate the immune system. Remarkably, serum concentrations of myokines such as IL-7 and IL-15 are inversely correlated with age, suggesting a link between skeletal muscle and age-dependent loss of immune system function.

As humans age, the immune system undergoes drastic changes. The umbrella term immune senescence is used to encompass these changes. Moreover, ageing is associated with increased serum levels of pro-inflammatory molecules. Skeletal muscle exhibits immune regulatory properties and that chronic, low-grade inflammation may induce muscle wasting. The concept of skeletal muscle as a regulator of immune function is relatively new and adds a new layer of complexity to the muscle-immune system link. Consequently, the muscle-immune system connection might be bidirectional: chronic, low-grade inflammation induces muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secretome. Concurrently, homeostasis of skeletal muscle is, in part, responsible for healthy immune function. However, when dysregulated, insufficient myokine signalling, alteration of membrane bound factors towards a pro-inflammatory profile and impaired regenerative capacities of immune cells might result in disruption of immune system function.

We propose that biological aging may disturb the equilibrium of muscle-immune system homeostasis with skeletal muscle acting as a potential central link between sarcopenia and immune senescence. Healthy muscle function is gradually lost in an aging biological system due to physical inactivity, metabolic changes and the accumulation of chronic, low-grade inflammation. In turn, impaired muscle function curtails skeletal muscle cell signalling needed for immune regulation and maintenance, culminating in a vicious cycle in which immune and muscle system dysfunction sustain each other.



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