Proteomics Analysis of Human Skeletal Muscle Reveals Novel Abnormalities in Obesity and Type 2 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 1; pp. 33 - 42
• Main Authors: Hwang, Hyonson, Bowen, Benjamin P., Lefort, Natalie, Flynn, Charles R., De Filippis, Elena A., Roberts, Christine, Smoke, Christopher C., Meyer, Christian, Højlund, Kurt, Yi, Zhengping, Mandarino, Lawrence J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2010
• Subjects: Adult; Analysis; Biological and medical sciences; Biopsy; Body Mass Index; Chaperonin Containing TCP-1 - genetics; Chaperonins - genetics; Cytoskeletal Proteins - genetics; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Glucose Clamp Technique; Health aspects; Humans; Hypotheses; Insulin resistance; Male; Mass Spectrometry; Medical sciences; Metabolic diseases; Metabolism; Middle Aged; Mitochondria, Muscle - metabolism; Muscle, Skeletal - physiopathology; Muscles; Musculoskeletal system; Obesity; Obesity - genetics; Original; Pathogenesis; Peptide Hydrolases - genetics; Physiological aspects; Proteins; Proteomics; Proteomics - methods; Reference Values; Reproducibility; Research design; Scientific imaging; Skeletal muscle; Striated muscle. Tendons; Type 2 diabetes; Vertebrates: osteoarticular system, musculoskeletal system; Endocrinopathy; Type 2 diabetes; Human; Obesity; Nutrition disorder; Metabolic diseases; Striated muscle; Nutritional status
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db09-0214

Proteomics Analysis of Human Skeletal Muscle Reveals Novel Abnormalities in Obesity and Type 2 Diabetes Hyonson Hwang 1 , 2 , Benjamin P. Bowen 1 , 3 , Natalie Lefort 1 , 2 , Charles R. Flynn 1 , Elena A. De Filippis 1 , Christine Roberts 1 , Christopher C. Smoke 1 , Christian Meyer 1 , Kurt Højlund 1 , 4 , Zhengping Yi 1 , 5 and Lawrence J. Mandarino 1 , 2 , 5 1 Center for Metabolic Biology, Arizona State University, Tempe, Arizona; 2 Department of Kinesiology, Arizona State University, Tempe, Arizona; 3 Harrington Department of Bioengineering, Arizona State University, Tempe, Arizona; 4 Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark; 5 School of Life Sciences, Arizona State University, Tempe, Arizona. Corresponding author: Lawrence J. Mandarino, lawrence.mandarino{at}asu.edu . Abstract OBJECTIVE Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Studies of insulin resistance usually are highly focused. However, approaches that give a more global picture of abnormalities in insulin resistance are useful in pointing out new directions for research. In previous studies, gene expression analyses show a coordinated pattern of reduction in nuclear-encoded mitochondrial gene expression in insulin resistance. However, changes in mRNA levels may not predict changes in protein abundance. An approach to identify global protein abundance changes involving the use of proteomics was used here. RESEARCH DESIGN AND METHODS Muscle biopsies were obtained basally from lean, obese, and type 2 diabetic volunteers ( n = 8 each); glucose clamps were used to assess insulin sensitivity. Muscle protein was subjected to mass spectrometry–based quantification using normalized spectral abundance factors. RESULTS Of 1,218 proteins assigned, 400 were present in at least half of all subjects. Of these, 92 were altered by a factor of 2 in insulin resistance, and of those, 15 were significantly increased or decreased by ANOVA ( P < 0.05). Analysis of protein sets revealed patterns of decreased abundance in mitochondrial proteins and altered abundance of proteins involved with cytoskeletal structure (desmin and alpha actinin-2 both decreased), chaperone function (TCP-1 subunits increased), and proteasome subunits (increased). CONCLUSIONS The results confirm the reduction in mitochondrial proteins in insulin-resistant muscle and suggest that changes in muscle structure, protein degradation, and folding also characterize insulin resistance. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received February 19, 2009. Accepted October 3, 2009. © 2010 American Diabetes Association