Schimke, Jill Coenen

Experimental evidence indicates that a lower synthesis rate of muscle contractile protein myosin heavy chain (MHC) occurs in age-related muscle wasting and weakness. To determine the molecular mechanism of this lower synthesis of MHC, we measured transcript levels of isoforms of MHC (MHCI, MHCIIa, and MHCIIx) in muscle biopsy samples of 7 young (20–27 yr), 12 middle-aged (47–60 yr), and 14 older (>65 yr) people. We further determined the effect of 3 mo of resistance exercise training (exercise) vs. nonintervention (control) on transcript levels of MHC isoforms on these subjects and the fractional synthesis rate (FSR) of MHC in 39 people aged 46–79 yr. MHCI mRNA levels did not significantly change with age, but MHCIIa decreased 38% ( P < 0.05) from young to middle age and further decreased 50% ( P < 0.05) from middle to old age. MHCIIx decreased 84% ( P < 0.05) from young to middle age and 48% from middle to old age ( P < 0.05). Exercise increased FSR of MHC by 47% ( P < 0.01) and mixed muscle protein by 56% ( P < 0.05). Exercise training results in an increase (85%) in transcript levels of MHCI and a decrease in the transcript levels of MHCIIa and MHCIIx. In conclusion, an age-related lowering of the transcript levels of MHCIIa and MHCIIx is not reversed by exercise, whereas exercise results in a higher synthesis rate of MHC in association with an increase in MHCI isoform transcript levels.

Type 2 diabetes is characterized by muscle insulin resistance. Nondiabetic first-degree relatives of type 2 diabetic patients have also been reported to have insulin resistance. A polygenic basis for pathogenesis of type 2 diabetes has been proposed. A gene expression profile was evaluated in the skeletal muscle of patients with type 2 diabetes while not on treatment for 2 weeks and after 10 days of intensive insulin treatment. Comparison of gene expression pattern with age-, sex-, and BMI-matched people with no family history of diabetes was performed using a microarray technique (Hu6800 arrays; Affymetrix, Santa Clara, CA). Only those gene transcripts showing ≥1.9-fold changes and an average difference in fluorescence intensity of ≥1,000 in all subjects are reported. Insulin sensitivity (SI) was measured using an intravenous glucose tolerance test. Of 6,451 genes surveyed, transcriptional patterns of 85 genes showed alterations in the diabetic patients after withdrawal of treatment, when compared with patterns in the nondiabetic control subjects. Insulin treatment reduced the difference in patterns between diabetic and nondiabetic control subjects (improved) in all but 11 gene transcripts, which included genes involved in structural and contractile functions, growth and tissue development, stress response, and energy metabolism. These improved transcripts included genes involved in insulin signaling, transcription factors, and mitochondrial maintenance. However, insulin treatment altered the transcription of 29 additional genes involved in signal transduction; structural and contractile functions; growth and tissue development; and protein, fat, and energy metabolism. Type 2 diabetic patients had elevated circulating insulin during the insulin-treated phase, although their blood glucose levels (98.8 ± 6.4 vs. 90.0 ± 2.9 mg/dl for diabetic vs. control) were similar to those of the control subjects. In contrast, after withdrawal of treatment, the diabetic patients had reduced SI and elevated blood glucose (224.0 ± 26.2 mg/dl), although their insulin levels were similar to those of the nondiabetic control subjects. This study identified several candidate genes for muscle insulin resistance, complications associated with poor glycemic control, and effects of insulin treatment in people with type 2 diabetes.