166-OR: Lower Response of Connective Tissue Growth Factor (CTGF) to Exercise Characterizes Insulin Resistant Muscle

Abstract

This study was undertaken to identify transcription factors that differentially respond to exercise in insulin resistance. Candidate transcription factors were identified from analysis of 5’-untranslated regions (5’-UTRs) of exercise responsive genes and from analysis of the 5’-UTRs of genes coding for proteins that differ in abundance in insulin resistance. Muscle biopsies were obtained from lean and obese subjects before, 30 min and 240 h. after a single exercise bout. Insulin sensitivity was assessed through glucose clamps. Obese subjects (n=8) were insulin resistant compared to lean (n=12) (7.0 ± 0.95 vs. 11.3 ± 0.8 mg∙kg FFM-1∙min-1, P<0.05) but performed exercise at the same intensity (VO2peak 35.0 ± 1.9 vs. 35.2 ± 3.9 ml∙min-1∙kg FFM-1, NS). Statistical over-representation analyses showed that proteins differing in abundance between healthy and insulin resistant resting muscle included those involved in mitochondrial function, protein targeting and translation, and metabolism. Transcription factor enrichment analysis of genes coding for these proteins revealed new candidate transcription factors. Q-rt-PCR analysis from pre and post-exercise muscle biopsies revealed several transcription and growth factors had altered responses to exercise in insulin resistant subjects, including EGR3, RELA, ATF2 and SP1. We previously showed that higher CTGF abundance and expression were associated with insulin resistance induced by a lipid emulsion infusion, along with extracellular matrix reorganization and tissue remodeling. Here, CTGF mRNA responded briskly 30 min after exercise in insulin sensitive but not insulin resistant subjects (4.7 ± 1.0 vs. 1.0 ± 0.22), returning to near-basal levels in both groups after 24 h. The lower response of CTGF expression to exercise in insulin resistance suggests that it may mediate the capacity of muscle to remodel itself following exercise, and partially explain the exercise resistance associated with insulin resistance. Disclosure R. Zapata Bustos: None. P.R. Langlais: None. D.K. Coletta: None. E.A. De Filippis: None. D. Grandjean: None. L. Mandarino: None. Funding National Institutes of Health (R01DK047936, DK066483, R01DK094013)