Dysregulated Autophagy Mediates Sarcopenic Obesity and Its Complications via AMPK and PGC1α Signaling Pathways: Potential Involvement of Gut Dysbiosis as a Pathological Link

Abstract

Sarcopenic obesity (SOB), which is closely related to being elderly as a feature of aging, is recently gaining attention because it is associated with many other age-related diseases that present as altered intercellular communication, dysregulated nutrient sensing, and mitochondrial dysfunction. Along with insulin resistance and inflammation as the core pathogenesis of SOB, autophagy has recently gained attention as a significant mechanism of muscle aging in SOB. Known as important cellular metabolic regulators, the AMP-activated protein kinase (AMPK) and the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathways play an important role in autophagy, inflammation, and insulin resistance, as well as mutual communication between skeletal muscle, adipose tissue, and the liver. Furthermore, AMPK and PGC-1α signaling pathways are implicated in the gut microbiome–muscle axis. In this review, we describe the pathological link between SOB and its associated complications such as metabolic, cardiovascular, and liver disease, falls and fractures, osteoarthritis, pulmonary disease, and mental health via dysregulated autophagy controlled by AMPK and/or PGC-1α signaling pathways. Here, we propose potential treatments for SOB by modulating autophagy activity and gut dysbiosis based on plausible pathological links.

Dietary curcumin restores insulin homeostasis in diet-induced obese aged mice

“…Interestingly, the autophagy pathway was also influenced by curcumin supplementation of both NCD and HFHSD based on GO-term and pathway enrichment analysis. Autophagy and the insulin signaling pathway are inextricably linked [30,31]. Recent studies have demonstrated that upregulating autophagy genes lead to amelioration of insulin resistance and enhancement of insulin sensitivity in obese mice [32][33][34].…”

Mechanisms Involved in Gut Microbiota Regulation of Skeletal Muscle

“…The AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-coactivator- (PGC-) 1 signaling pathways are known to regulate cellular metabolism and play essential roles in autophagy, inflammation, insulin resistance, and skeletal muscle. In addition, AMPK and PGC-1 α signaling pathways are associated with the gut microbiota–muscle axis [ 68 ]. The activation of AMPK and PGC-1 decreases with age [ 69 ], and inhibition of AMPK and PGC-1 α signaling pathways decreases autophagic activity, leading to a decrease in skeletal muscle mass and function [ 70 ].…”

“…The NF- κ B signaling mentioned above also stimulates the production of NLRP3 inflammasomes [ 73 ]. Thus, dysregulated autophagic activity and inflammatory responses play a pivotal part in the loss of skeletal muscle mass and function, and AMPK and PGC-1 α signaling pathways are closely associated with the gut microbiota–muscle axis [ 68 ]. Further research into the relationships between the AMPK and PGC-1 signaling pathways, autophagy, inflammatory responses, and the gut microbiome could aid in the treatment of disorders characterized by skeletal muscle mass and function loss ( Figure 1 ).…”

Gut Microbiota: A Key Regulator in the Effects of Environmental Hazards on Modulates Insulin Resistance

“…The online Kyoto Encyclopedia of Genes and Genomes (KEGG) database ( ) summarizes that the following pathways may underlie insulin resistance: (i) in muscle cells, GLUT4 translocation and glucose uptake are inhibited through the PI3K/AKT2/mTOR pathway perturbation; (ii) in liver cells, gluconeogenic genes are increased, whereas glycogen production is reduced by the perturbation of the IRS/GSK-3 pathway; and (iii) there is increased activity of phosphatases, including PTPs, PTEN, and PP2A. Meanwhile, oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives, and inflammation also contribute to insulin resistance ( Genders et al., 2020 ; Ryu et al., 2020 ; Sharma et al., 2020 ).…”