Manickam R, Duszka K, Wahli W

Int J Mol Sci 2020;21. doi: 10.3390/ijms21218056
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Published October 19, 2020 review by Gérard Bozet, MD
Posted December 9, 2020

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 specialised responses upon activation by their ligands. 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. The human gastrointestinal tract is inhabited by many types of microbiota. Dysregulations of their microenvironment are associated with various health problems, not only limited to gastrointestinal disorders, such as inflammatory bowel disease, but to impacts beyond the intestine. For example, intestinal microbiota can affect the liver in non-alcoholic fatty liver disease, visceral adipose tissue during adipogenesis, and the heart in atherosclerosis. The factors contributing to these pathogeneses involve the gut microbiota and the effector organs of the host, and everything in between. The PPARs are pivotal for the modulation of many of the pathogeneses mentioned above. It is, therefore, conceivable that, in the process of host-microbiota interactions, PPARs play an important role.

Manickam R, Duszka K, Wahli W. PPARs and Microbiota in Skeletal Muscle Health and Wasting. Int J Mol Sci 2020;21. doi: 10.3390/ijms21218056.

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