title: Altered Skeletal Muscle Mitochondrial Proteome As the Basis of Disruption of Mitochondrial Function in Diabetic Mice.
abstract: Insulin plays pivotal role in cellular fuel metabolism in skeletal muscle. Despite being the primary site of energy metabolism, the underlying mechanism on how insulin deficiency deranges skeletal muscle mitochondrial physiology remains to be fully understood. Here we report an important link between altered skeletal muscle proteome homeostasis and mitochondrial physiology during insulin deficiency. Deprivation of insulin in streptozotocin-induced diabetic mice decreased mitochondrial ATP production, reduced coupling and phosphorylation efficiency, and increased oxidant emission in skeletal muscle. Proteomic survey revealed that the mitochondrial derangements during insulin deficiency were related to increased mitochondrial protein degradation and decreased protein synthesis, resulting in reduced abundance of proteins involved in mitochondrial respiration and β-oxidation. However, a paradoxical upregulation of proteins involved in cellular uptake of fatty acids triggered an accumulation of incomplete fatty acid oxidation products in skeletal muscle. These data implicate a mismatch of β-oxidation and fatty acid uptake as a mechanism leading to increased oxidative stress in diabetes. This notion was supported by elevated oxidative stress in cultured myotubes exposed to palmitate in the presence of a β-oxidation inhibitor. Together, these results indicate that insulin deficiency alters the balance of proteins involved in fatty acid transport and oxidation in skeletal muscle, leading to impaired mitochondrial function and increased oxidative stress.
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Piotr
authors.initials: P
authors.lastname: Zabielski
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Lanza
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Gopala
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Carrie J Holtz
authors.initials: CJ
authors.lastname: Heppelmann
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Bergen
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN.
authors.forename: Surendra
authors.initials: S
authors.lastname: Dasari
authors.affiliation: Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, MN nair@mayo.edu.
authors.forename: K Sreekumaran
authors.initials: KS
authors.lastname: Nair
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006861:Hydrogen Peroxide / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D015151:Immunoblotting; D007328:Insulin / Q000627:therapeutic use; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010101:Oxygen Consumption; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D052097:Quadriceps Muscle / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D020543:Proteome; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide