Proteome analysis reveals phosphorylation of ATP synthase beta -subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes.
Insulin resistance in skeletal muscle is a hallmark feature of type 2 diabetes. An increasing number of enzymes and metabolic pathways have been implicated in the development of insulin resistance. However, the primary cellular cause of insulin resistance remains uncertain. Proteome analysis can quantitate a large number of proteins and their post-translational modifications simultaneously and is a powerful tool to study polygenic diseases like type 2 diabetes. Using this approach on human skeletal muscle biopsies, we have identified eight potential protein markers for type 2 diabetes in the fasting state. The observed changes in protein expression indicate increased cellular stress, e.g. up-regulation of two heat shock proteins, and perturbations in ATP (re)synthesis and mitochondrial metabolism, e.g. down-regulation of ATP synthase beta-subunit and creatine kinase B, in skeletal muscle of patients with type 2 diabetes. Phosphorylation appears to play a key, potentially coordinating role for most of the proteins identified in this study. In particular, we demonstrated that the catalytic beta-subunit of ATP synthase is phosphorylated in vivo and that the levels of a down-regulated ATP synthase beta-subunit phosphoisoform in diabetic muscle correlated inversely with fasting plasma glucose levels. These data suggest a role for phosphorylation of ATP synthase beta-subunit in the regulation of ATP synthesis and that alterations in the regulation of ATP synthesis and cellular stress proteins may contribute to the pathogenesis of type 2 diabetes.
Højlund
Kurt
K
Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Denmark.
Wrzesinski
Krzysztof
K
Larsen
Peter Mose
PM
Fey
Stephen J
SJ
Roepstorff
Peter
P
Handberg
Aase
A
Dela
Flemming
F
Vinten
Jørgen
J
McCormack
James G
JG
Reynet
Christine
C
Beck-Nielsen
Henning
H
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000328:Adult; D000595:Amino Acid Sequence; D015415:Biomarkers; D001786:Blood Glucose / Q000032:analysis; D024141:Collagen Type IV / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000628:therapy; D005215:Fasting; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits / Q000032:analysis; D020543:Proteome; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism*
D015415:Biomarkers; D001786:Blood Glucose; D024141:Collagen Type IV; D018841:HSP90 Heat-Shock Proteins; D021122:Protein Subunits; D020543:Proteome; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; D006180:Proton-Translocating ATPases