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

Abstract

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 on 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 non-pharmacological 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.

Ibuprofen Increases Markers of Intestinal Barrier Injury But Suppresses Inflammation at Rest and After Exercise in Hypoxia

“…Exercise in hypoxia increased TNF-α, IL-1β, and MCP-1 in both the placebo and ibuprofen trials (main effect of time). MCP-1 is a chemokine involved in the recruitment of various leukocytes (primarily monocytes) to sites of inflammation or injury, whereas TNF-α and IL-1β are proinflammatory cytokines, which play important roles in the immune/inflammatory response to LPS through the interaction with Toll-like receptor-4 (TLR-4) (40). Thus, the increases in TNF-α and IL-1β may be explained by exercise-induced LPS translocation, enhanced TLR-4 activation enabled by elevated sCD14 presenting LPS to TLR-4, or a combination of the two (40).…”

“…MCP-1 is a chemokine involved in the recruitment of various leukocytes (primarily monocytes) to sites of inflammation or injury, whereas TNF-α and IL-1β are proinflammatory cytokines, which play important roles in the immune/inflammatory response to LPS through the interaction with Toll-like receptor-4 (TLR-4) (40). Thus, the increases in TNF-α and IL-1β may be explained by exercise-induced LPS translocation, enhanced TLR-4 activation enabled by elevated sCD14 presenting LPS to TLR-4, or a combination of the two (40). Interestingly, although markers of intestinal injury and microbial translocation were higher, we report lower circulating markers of inflammation in the ibuprofen trial.…”

Effects of acute aerobic exercise on circulating sTLR and sRAGE profiles in normal‐ and abnormal‐glucose‐tolerant individuals

“…Ten TLRs (TLR1‐10) are expressed in human skeletal muscle (Nishimuru & Naito, 2005; Perkins et al., 1985; Pillon & Krook, 2017). Of the 10 TLRs that exist in humans, many function in line with RAGE as a result of recognizing similar PAMPs/DAMPs, convergence on the intracellular adaptor protein (i.e., Myd88), and activation of the NFκB pathway (Ducharme et al., 2022; Federico et al., 2020; Kawai & Akira, 2010; Nielsen et al., 2017). More specifically, TLR2 and TLR4 are two of the most highly expressed TLRs in human skeletal muscle (Perkins et al., 1985; Pillon & Krook, 2017) and each has been shown to recognize PAMPs/DAMPs that are commonly shown to be elevated in insulin‐resistant individuals, such as lipoproteins, high mobility group box 1 (HMGB1), lipopolysaccharide (LPS), and AGEs (Choi et al., 2012; Tsan & Goa, 2004).…”

“…Together, cRAGE and esRAGE comprise to the total soluble (sRAGE) population and once in the circulation are suspected to function similarly as sTLRs. Several studies have shown that aerobic exercise (AE) and stimulated muscle contractions augment circulating solubilized receptor concentrations (Choi et al., 2012; Ducharme et al., 2022; Kotani et al., 2011; Legaard et al., 2022; Santilli et al., 2013). While it is difficult to conclusively determine the origin of these solubilized receptors after appearing in the circulation, many tissues have been shown to contain or produce solubilized receptors (Henrick et al., 2016).…”

Effect of non-protein amino acids β-amino butyric acid (BABA) on the intestinal G- bacterial community

“…The monitoring-like receptor (TLR-4) belongs to the family of TLR which, when activated in cells of the body, initiates a chain of events (Mohamed et al, 2022). Toll-like receptor-4 is the primary receptor for LPS and is involved in the proin ammatory response, and Toll-like-4 is expressed by different types of cells throughout the human body (Ducharme et al, 2022). TLR-4 can be considered an important target for the treatment of febrile seizures in FS rats (Zaniani et al, 2022).…”