Peroxisomal-Mitochondrial Metabolic Interactions in Lipid Metabolism in Human Skeletal Muscle

Abstract

Peroxisomal activity and associated functions, including [beta]-oxidation contributions toward maintaining cellular lipid homeostasis, is poorly defined in extra hepatic tissues, most especially in human skeletal muscle (HSkM). Studies in skeletal muscle in both rodent and human models have demonstrated that high fat diet (HFD) can induce excess incompletely oxidized lipid species generated from mitochondria and accumulation of bioactive lipids, both which are associated with insulin resistance and Type 2 Diabetes. Peroxisomes and mitochondria have many similarities in terms of oxidization of fatty acids and peroxisomes are reputed to metabolically interact with mitochondria to maintain lipid homeostasis. However, progress in defining the role of peroxisomal function in skeletal muscle with respect to enhancing lipid disposal is based exclusively on rodent models. Despite the evidence for peroxisomal activity in skeletal muscle gained from rodents, a potential role for peroxisomal activity/function in HSkM is largely unknown. To address this void in the literature, lean and obese subjects of varying levels of intramyofibrilar lipid content were biopsied from the vastus lateralis pre- and 4 hours post- acute high fat liquid meal and 7 days after a solid food high fat diet. Skeletal muscle tissue and derived primary myotubes were utilized to 1) demonstrate that peroxisomal genes and peroxins proteins are associated with elevations in the cellular lipid environment in HSkM 2) demonstrate the biological interactions of peroxisomal activity in terms of mitochondrial oxidation of lipids and 3) demonstrate the role of the transcriptional co-activator PGC-1[Alpha] in the induction of peroxisomal activity and metabolic cooperation with mitochondria. With regard to the latter, we utilized a gain of function approach by overexpressing PGC-1[Alpha] in HSkM cells to support our hypothesis that like mitochondrial biogenesis, peroxisomal activity and subsequent responses is under the influence of PGC-1[Alpha]. We further hypothesized that PGC-1[Alpha] modulates metabolic interactions between peroxisomes and mitochondria in terms of fatty acid oxidation (FAO). Collectively, this is the first report associating lipid oversupply, intramyofibrilar lipid accumulation, peroxisomal activity, and mitochondrial oxidation of peroxisomal derived metabolites in HSkM. These novel findings demonstrate a functional cooperation between peroxisomes and mitochondria to enhance FAO suggesting a new paradigm in HSkM with respect to lipid catabolism under conditions of lipid overload. Furthermore, our mechanistic studies establishing the importance of PGC-1[Alpha] in mediating peroxisomal adaptations will likely provide fruitful insights into designing future investigations for developing novel strategies to treat obesity-related metabolic diseases.