Impairments in Site-Specific AS160 Phosphorylation and Effects of Exercise Training

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 10; pp. 3437 - 3447
• Main Authors: CONSITT, Leslie A, VAN METER, Jessica, NEWTON, Christopher A, COLLIER, David N, DAR, Moahad S, WOJTASZEWSKI, Jørgen F. P, TREEBAK, Jonas T, TANNER, Charles J, HOUMARD, Joseph A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2013
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adult; Aged; Aged, 80 and over; Aging - metabolism; Analysis; Biological and medical sciences; Blotting, Western; Cross-Sectional Studies; Diabetes; Diabetes research; Diabetes. Impaired glucose tolerance; Effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exercise; Female; Glucose Clamp Technique; GTPase-Activating Proteins - metabolism; Health aspects; Humans; Insulin - metabolism; Intervention; Male; Medical sciences; Middle Aged; Muscle, Skeletal - metabolism; Muscles; Nuclear Proteins - metabolism; Original Research; Phosphorylation; Physical Endurance; Physiological aspects; Resistance Training; Sedentary Lifestyle; Serine; Signal Transduction; Skeletal muscle; Threonine; Training; Endocrinopathy; Physical exercise; Phosphorylation; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db13-0229

The purpose of this study was to determine if site-specific phosphorylation at the level of Akt substrate of 160 kDa (AS160) is altered in skeletal muscle from sedentary humans across a wide range of the adult life span (18-84 years of age) and if endurance- and/or strength-oriented exercise training could rescue decrements in insulin action and skeletal muscle AS160 phosphorylation. A euglycemic-hyperinsulinemic clamp and skeletal muscle biopsies were performed in 73 individuals encompassing a wide age range (18-84 years of age), and insulin-stimulated AS160 phosphorylation was determined. Decrements in whole-body insulin action were associated with impairments in insulin-induced phosphorylation of skeletal muscle AS160 on sites Ser-588, Thr-642, Ser-666, and phospho-Akt substrate, but not Ser-318 or Ser-751. Twelve weeks of endurance- or strength-oriented exercise training increased whole-body insulin action and reversed impairments in AS160 phosphorylation evident in insulin-resistant aged individuals. These findings suggest that a dampening of insulin-induced phosphorylation of AS160 on specific sites in skeletal muscle contributes to the insulin resistance evident in a sedentary aging population and that exercise training is an effective intervention for treating these impairments.