PPARs and Microbiota in Skeletal Muscle Health and Wasting

Abstract

Skeletal muscle is a major metabolic organ that uses mostly glucose and lipids for energy production and has the capacity to remodel itself in response to exercise and fasting. Skeletal muscle wasting occurs in many diseases and during aging. Muscle wasting is often accompanied by chronic low-grade inflammation associated to inter- and intra-muscular fat deposition. During aging, muscle wasting is advanced due to increased movement disorders, as a result of restricted physical exercise, frailty, and the pain associated with arthritis. Muscle atrophy is characterized by increased protein degradation, where the ubiquitin-proteasomal and autophagy-lysosomal pathways, atrogenes, and growth factor signaling all play an important role. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of transcription factors, which are activated by fatty acids and their derivatives. PPARs regulate genes that are involved in development, metabolism, inflammation, and many cellular processes in different organs. PPARs are also expressed in muscle and exert pleiotropic specialized responses upon activation by their ligands. There are three PPAR isotypes, viz., PPARα, -β/δ, and -γ. The expression of PPARα is high in tissues with effective fatty acid catabolism, including skeletal muscle. PPARβ/δ is expressed more ubiquitously and is the predominant isotype in skeletal muscle. It is involved in energy metabolism, mitochondrial biogenesis, and fiber-type switching. The expression of PPARγ is high in adipocytes, but it is also implicated in lipid deposition in muscle and other organs. Collectively, all three PPAR isotypes have a major impact on muscle homeostasis either directly or indirectly. Furthermore, reciprocal interactions have been found between PPARs and the gut microbiota along the gut–muscle axis in both health and disease. Herein, we review functions of PPARs in skeletal muscle and their interaction with the gut microbiota in the context of muscle wasting.

Transcriptome sequencing and analysis reveals the molecular mechanism of skeletal muscle atrophy induced by denervation

“…Recently, lysosomes, containing many hydrolases and proteases, have been considered to play an important role in maintaining tissue homeostasis, mainly through autophagy, phagocytosis, and endocytosis (28). The ALS plays a key role in protein degradation in skeletal muscle cells (29,30).…”

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet

“…When animals receive a HFD and obesity occurs, the body's normal metabolism slows dramatically, and adaptive mechanisms often fail to give the body appropriate feedback. The resulting in ux of lipids from adipose tissue exceeds its storage capacity, leading to the accumulation of harmful lipids in skeletal muscle, which is thought to be an important factor in insulin resistance [17,18]. Most phospholipids exist in skeletal muscle membranes and are important regulators of skeletal muscle mitochondrial respiratory function [19,20].…”

A Pound of Flesh: What Cachexia Is and What It Is Not

“…However, due to the high interindividual variability observed in the human microbiota composition, additional controlled studies with larger sample sizes are needed to rule out a causal link [ 109 , 111 , 112 ]. Additional reports suggest a possible role of the gut microbiota in the regulation of PPARs and the peripheral muscle circadian clock [ 113 , 114 ]. The gut has been reported to also influence muscle loss in cancer-related cachexia due to the chronic inflammatory status underlying this specific condition as well as by directly causing nutrient malabsorption because of barrier dysfunctions or through alterations in ghrelin production and distribution [ 115 ].…”