This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Lessard, S. J. Articles by Hawley, J. A. PubMed PubMed Citation Articles by Lessard, S. J. Articles by Hawley, J. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Exercise for Children Exercise and Physical Fitness

Impaired Skeletal Muscle β-Adrenergic Activation and Lipolysis Are Associated with Whole-Body Insulin Resistance in Rats Bred for Low Intrinsic Exercise Capacity

School of Medical Sciences (S.J.L., D.A.R., J.A.H.), Royal Melbourne Institute of Technology, Bundoora 3083, Australia; St. Vincent’s Institute (Z.-P.C., B.J.v.D., B.E.K.), University of Melbourne, Fitzroy, Victoria 3065, Australia; Department of Physiology (M.J.W.), Monash University, Clayton 3800, Australia; and University of Michigan (L.G.K., S.L.B.), Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Sarah J. Lessard, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215. E-mail: sarah.lessard{at}joslin.harvard.edu.

Rats selectively bred for high endurance running capacity (HCR) have higher insulin sensitivity and improved metabolic health compared with those bred for low endurance capacity (LCR). We investigated several skeletal muscle characteristics, in vitro and in vivo, that could contribute to the metabolic phenotypes observed in sedentary LCR and HCR rats. After 16 generations of selective breeding, HCR had approximately 400% higher running capacity (P < 0.001), improved insulin sensitivity (P < 0.001), and lower fasting plasma glucose and triglycerides (P < 0.05) compared with LCR. Skeletal muscle ceramide and diacylglycerol content, basal AMP-activated protein kinase (AMPK) activity, and basal lipolysis were similar between LCR and HCR. However, the stimulation of lipolysis in response to 10 µM isoproterenol was 70% higher in HCR (P = 0.004). Impaired isoproterenol sensitivity in LCR was associated with lower basal triacylglycerol lipase activity, Ser660 phosphorylation of HSL, and β2-adrenergic receptor protein content in skeletal muscle. Expression of the orphan nuclear receptor Nur77, which is induced by β-adrenergic signaling and is associated with insulin sensitivity, was lower in LCR (P < 0.05). Muscle protein content of Nur77 target genes, including uncoupling protein 3, fatty acid translocase/CD36, and the AMPK 3 subunit were also lower in LCR (P < 0.05). Our investigation associates whole-body insulin resistance with impaired β-adrenergic response and reduced expression of genes that are critical regulators of glucose and lipid metabolism in skeletal muscle. We identify impaired β-adrenergic signal transduction as a potential mechanism for impaired metabolic health after artificial selection for low intrinsic exercise capacity.