Exercise mitigates the Toll of muscle atrophy: a narrative review of the effects of exercise on Toll-like receptor-4 in leukocytes and skeletal muscle

Conditions characterized by muscle wasting such as cachexia and sarcopenia are devastating at the individual level, and they place a profound burden on public health. Evidence suggests that inflammation is likely a mechanistic contributor to the pathogenesis of these conditions. One specific molecule, lipopolysaccharide, has gained attention due to its role in initiating inflammation. Toll-like receptor-4 is the primary receptor for lipopolysaccharide and has been shown to be implicit in the downstream proinflammatory response associated with lipopolysaccharide. Importantly, Toll-like receptor-4 is expressed in various cell types throughout the human body such as leukocytes and skeletal muscle fibers and may have site-specific effects that contribute to muscle wasting conditions based on the location in which activation occurs. Accordingly, reducing proinflammatory signaling at these locations may be an effective strategy at mitigating muscle wasting. Regular exercise training is believed to elicit anti-inflammatory adaptations, but the mechanisms by which this occurs are yet to be fully understood. Understanding the mechanisms by which Toll-like receptor-4 activation contributes to muscle wasting and how exercise affects this may allow for the development of a nonpharmacological therapeutic intervention. Therefore, in this review, we summarize the current understanding of the lipopolysaccharide/Toll-like receptor-4 axis in leukocytes and skeletal muscle fibers on the pathogenesis of muscle wasting conditions and we critically examine the current evidence regarding the effects of exercise on this axis.