Active Voice: Uncovering Important Regulators of Skeletal Muscle Fat Metabolism
By: Harrison Stierwalt, Ph.D., and Sean Newsom, Ph.D.

Skeletal muscle fat metabolism has emerged as a critical area of study relevant to human health and disease. Excessive weight gain contributes to the development of insulin resistance, which increases risk for numerous chronic diseases including type 2 diabetes, cardiovascular diseases and even certain cancers. Alterations to the use of fat for energy (i.e., fat oxidation) and fat accumulation within skeletal muscle are thought to be major contributors to the development of insulin resistance. The continued worldwide rise in prevalence of overweight or obesity highlights the growing need to identify approaches, such as exercise, and regulatory mechanisms that can serve to improve skeletal muscle fat metabolism.

In two studies recently published in Medicine & Science in Sports & Exercise® (MSSE), we turned our attention to the long-chain acyl-coenzyme A synthetase (ACSL) family of proteins. We investigated these proteins because when fatty acids enter a skeletal muscle cell, they must first be modified by an ACSL enzyme prior to being trafficked into oxidation or storage pathways. Mechanistic studies employing genetic manipulation techniques have indicated different ACSL proteins (i.e., isoforms, such as ACSL1 and ACSL6) may have unique roles. These different isoforms may either facilitate fat oxidation or promote fat storage.

Our study, which published in the March 2021 issue of MSSE, was among the first to explore physiologic roles of ACSL proteins in regulation of fat metabolism in humans. In a study of lean, sedentary participants (10 females and four males), we sought to determine which ACSL proteins could be detected in human skeletal muscle. Additionally, we studied the impact of acute aerobic exercise on ACSL protein abundance and associations between ACSL proteins and measures of skeletal muscle fat metabolism. Participants completed metabolic study visits with skeletal muscle biopsies obtained at rest and following a single session of moderate-intensity cycling exercise. We found that four of the five known ACSL isoforms were readily detectable in human skeletal muscle, including preliminary evidence that females may exhibit greater ACSL protein abundance compared with males. We observed minimal impact of acute aerobic exercise on ACSL protein abundance. However, we identified positive relationships between ACSL1 and whole-body fat oxidation measured during exercise and between ACSL6 and skeletal muscle fat storage.

Our current findings build upon our previous investigation published in the March 2020 issue of MSSE. In that study we showed that both diet-induced obesity and endurance exercise training can alter the protein abundance of specific ACSLs in the skeletal muscle of mice.

Taken together, our findings support the mounting body of evidence indicating pivotal and unique roles of ACSL proteins as regulators of skeletal muscle fat metabolism. Such roles for ACSL proteins in regulation of skeletal muscle fat metabolism may ultimately prove to be promising targets for prevention or treatment of obesity-related insulin resistance. By extending understanding of ACSL proteins to healthy humans, we also highlight that there is still much to be uncovered in this emerging area of research. We hope our findings further motivate the field to help advance understanding regarding the roles of skeletal muscle ACSL protein function in humans.

About the authors:
Harrison Stierwalt, Ph.D., completed his doctoral training at Oregon State University under the mentorship of Sean Newsom, Ph.D., and Matthew Robinson, Ph.D. Dr. Stierwalt is currently a post-doctoral fellow at the University of Kansas Medical Center working with John Thyfault, Ph.D. His research focuses on improving human health using exercise as an intervention to identify potential therapeutic targets in skeletal muscle and liver. Connect with Dr. Stierwalt at hstierwalt@kumc.edu.

Sean Newsom, Ph.D., is an assistant professor of Kinesiology and co-director of the Translational Metabolism Research Laboratory at Oregon State University. Dr. Newsom’s research seeks to identify the molecular and cellular basis of insulin resistance in obesity, including how exercise activity can improve insulin action, focusing on the roles of lipid and mitochondrial metabolism in skeletal muscle. He is a member of ACSM and serves on the Research Review Committee. Connect with Dr. Newsom at sean.newsom@oregonstate.edu, and learn more about his research at health.oregonstate.edu/tmrl.

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