Aerobic Training Remodels Muscle Lipid Composition and Improves Intrinsic Mitochondrial Function in Men with Type 2 Diabetes

Abstract

The effects of exercise training on the skeletal muscle (SKM) lipidome and mitochondrial function have not been thoroughly explored in individuals with type 2 diabetes (T2D). We investigated the effects of exercise training on molecular signatures within SKM of T2D, employing integrated multi-omics data analyses including lipidomics [MS/MS-shotgun], global DNA methylation and transcriptomics [RNA-Seq]. Muscle tissue and cellular mitochondrial respiration was quantified by high resolution respirometry. Ten weeks of aerobic training increased monolysocardiolipin (MLCL), a marker of mitochondrial remodeling, reduced total and specific species of sphingomyelin (SM), phosphatidylserine (PS) and ceramides lipid content and improved intrinsic mitochondrial respiration in SKM of T2D without alterations in mitochondrial DNA copy number or cardiolipin content. Exercise training differentially modified 50 DNA methylation sites. Among these genes, NOX4, acts as an oxygen sensor and catalyzes the reduction of reactive oxygen species (ROS), and PLCE1, catalyzes the hydrolysis of phosphoinositol 1,4,5-triphosphate (IP3) and DAG, were hypo-methylated and hyper-methylated, respectively, following training. Exercise training differentially regulated 70 transcripts in SKM of T2D that resulted in enrichments of lipid and amino acid metabolism and β-oxidation pathways. In summary, aerobic training improves intrinsic and cell autonomous SKM mitochondrial function and modifies SKM lipid composition in men with T2D, with potentially advantageous augmentations of oxidative stress and insulin signaling pathways. Disclosure M.F. Pino: None. N. Stephens: None. F. Yi: None. A.P. Hodges: None. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc.. S.R. Smith: None. B.H. Goodpaster: None. L.M. Sparks: None.