Importance of the Innate Immune Response in Skeletal Muscle to Sepsis-Induced Alterations in Protein Balance

Abstract

There is growing appreciation that skeletal muscle is a fully functional component of the body's innate immune system with the potential to actively participate in the host response to invading bacteria as opposed to being a passive target. In this regard, skeletal muscle in general and myocytes specifically possess an afferent limb that recognizes a wide variety of host pathogens via their interaction with multiple classes of cell membrane–bound and intracellular receptors, including toll-like receptors, cytokine receptors, NOD-like receptors, and the NLRP inflammasome. The efferent limb of the innate immune system in muscle is equally robust and with an increased synthesis and secretion of a variety of myocyte-derived cytokines (i.e., myokines), including TNF-α, IL-1, IL-6, and NO as well as multiple chemokines in response to appropriate stimulation. Herein, the current narrative review focuses primarily on the immune response of myocytes per se as opposed to other cell types within whole muscle. Moreover, because there are important differences, this review focuses specifically on systemic infection and inflammation as opposed to the response of muscle to direct injury and various types of muscular dystrophies. To date, however, there are few definitive muscle-specific studies that are necessary to directly address the relative importance of muscle-derived immune activation as a contributor to either the systemic immune response or the local immune microenvironment within muscle during sepsis and the resultant downstream metabolic disturbances.

Loss of ZBED6 Protects Against Sepsis‐Induced Muscle Atrophy by Upregulating DOCK3‐Mediated RAC1/PI3K/AKT Signaling Pathway in Pigs

“…Inflammation is one of the main drivers of sepsis‐induced muscle atrophy. [ 2 , 25 ] Here, we found that both septic WT and ZBED6 −/− pigs developed persistent fever (Figure S4A , Supporting Information), leukocytosis, and neutrophilia (Figure S4B,C , Supporting Information), as well as similar mRNA levels of inflammatory marker genes IL‐6, TNF‐a, NLRP3, and TLR4 in skeletal muscle (Figure S4D–F , Supporting Information). These results demonstrated that ZBED6 expression is not related to inflammatory, excluding a potential contribution of attenuation of systemic or skeletal muscle specific inflammation to the protection of sepsis‐induced muscle atrophy by ZBED6 deletion.…”

“…Up to 90% of severe sepsis patients have muscle atrophy that hampers weaning from ventilatory support, delays rehabilitation, and is associated with an increased risk of death. [ 1 ] Although various contributing factors such as inflammation, [ 2 ] oxidative stress [ 3 ] and mitochondrial dysfunction, [ 4 ] and protein metabolism imbalance [ 5 ] have been identified, the molecular regulators involved in modulating muscle atrophy remain poorly understood. Several animal models, such as pig, [ 6 ] rat, [ 7 ] and mouse, [ 8 ] have played a crucial role in advancing our knowledge of sepsis‐induced muscle atrophy.…”

The Contribution of Muscle Innate Immunity to Uremic Cachexia

“…There is an increasing understanding of the role played by skeletal muscle in the immune response and inflammation, mainly on the activation of the innate immune system in muscle [ 24 , 25 ]. According to an emergent hypothesis, skeletal muscle is now regarded as a component of the innate immune system, with primary importance in the response to bacterial infection, as summarized in Figure 1 .…”

“…called metabolism-associated molecular patterns (MAMPS) are capable of activating PRRs [ 26 ]. Toll-like receptors (TLRs), which are a major component of the native immunity afferent limb ( Figure 1 ) [ 28 ], can activate transcription factors that up-regulate the expression of pro-inflammatory cytokines in several cell types and tissues, including skeletal muscle [ 25 , 26 , 27 , 28 ]. Both TLRs’ functions and signaling are dependent on their location, with receptors located on the cell surface (i.e., TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10) usually recognizing pathogenic components, such as proteins (LPS and flagellin) or lipids (mainly lipoproteins).…”

“…Pathogenic microorganisms that escape initial detection can be present intra-cellularly and can be recognized by specialized NLRs. For example, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), which serve as intra-cellular pathogen sensors in immune tissues, are also found in muscle [ 25 ]. NOD1 and NOD2 detect bacteria-specific peptidoglycans (γ-d-glu-meso-diaminopimelic acid and muramyl dipeptide (MDP), respectively), resulting in the up-regulation of pro-inflammatory signaling pathways via the activation of the nuclear factor κ light-chain enhancer of activated B cells (NF-κB) [ 26 , 27 ].…”