The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis

Abstract

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been demonstrated to have lipid-lowering and anti-diabetic actions. This review will aim to provide a comprehensive overview of the functions of PPARs in energy homeostasis, with a focus on the impacts of PPAR agonism on muscle metabolism and function. The dysregulation of energy homeostasis in skeletal muscle is a frequent underlying characteristic of inflammation-related conditions such as sepsis. However, the potential benefits of PPAR agonism on skeletal muscle protein and fuel metabolism under these conditions remains under-investigated and is an area of research opportunity. Thus, the effects of PPARγ agonism on muscle inflammation and protein and carbohydrate metabolism will be highlighted, particularly with its potential relevance in sepsis-related metabolic dysfunction. The impact of PPARδ agonism on muscle mitochondrial function, substrate metabolism and contractile function will also be described.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy

“…In recent years, various in vitro and in vivo studies have reported that all isoforms of PPARs primarily regulate lipid and glucose metabolism and have additional regulatory roles in cell proliferation and differentiation, vascular homeostasis and atherosclerosis, cancer, and the immune system (38,47). In addition to the mentioned activities, it is thought that the activation of PPAR subtypes reduces the expression of proinflammatory cytokines and inflammatory cell functions, exerting significant anti-inflammatory properties (48). PPARa is the first known PPAR that was initially cloned from a mouse liver complementary DNA library as a nuclear receptor that mediates the effects of an endogenous group and xenobiotic compounds known as peroxisome proliferators (PPs) (31,49).…”

“…PPARa is mainly involved in the carbohydrate metabolism and catabolism of fatty acids and their oxidation, such that its activation reduces lipid levels (52-55). Additionally, it has been well highlighted that PPARa increases the expression of IkB, which is a factor that suppresses the nuclear translocation and transcriptional activity of NF-kB, thereby interfering with NF-kB signaling and the inflammatory response (48). Besides, increasing evidence has demonstrated that the anti-inflammatory properties of PPARa are manifested by a decrease in the secretion of several key downstream inflammatory factors such as NF-kB-driven cytokines (TNF-a, IL1B, and IL6), COX2, IL8, IL12, IL2, VCAM1, TLR4, MCP1, STAT3, AP-1, and IL18 (56,57).…”

Effect of Supplementation with Omega-3 Polyunsaturated Fatty Acids on Metabolic Modulators in Skeletal Muscle of Rats with an Obesogenic High-Fat Diet

“…Previous studies indicate that the insulin-sensitizing effect in adipose tissue could be due to various mechanisms. For example, ω-3 PUFAs are anti-inflammatory, stimulate fatty acid oxidation, and modulate mitochondrial function [ 46 , 47 ]. Furthermore, studies in macrophages, mature adipocytes, and mice suggest that G protein-coupled receptor 120 (GPR120) is the most important mediator of the effects of ω-3 PUFA [ 48 , 49 ]; however, this receptor is not expressed in muscle.…”

Immune system modulation in aging: Molecular mechanisms and therapeutic targets

“…Transfection of lentiviral siRNA against AP-1 in mice fed with high-fat diet resulted in the alleviation of systemic and hepatic inflammation ( 87 ). Interestingly, the use of rosiglitazone, a PPARγ agonist, was found to exert a positive effect on animals with sepsis, decreasing cell death and cardiac inflammation; furthermore, increased fatty acid oxidation and improved insulin resistance were also observed in human skeletal muscle ( 88 ). Since aging is a very complex process that involves different biological processes, therapies aimed to modulate inflammaging have to be focused on the synergic effect of more than one compound, to regulate simultaneously different pathways.…”