PGC-1 & Muscle Mitochondrial Dysfunction in Diabetes

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DESCRIPTION (provided by applicant): We discovered a phenomenon called "exercise resistance", where insulin resistant individuals do not respond normally to a single bout of exercise with respect to expression of PGC-1α and other genes). To generate hypotheses regarding why this happens, normal glucose tolerant volunteers had one exercise bout with muscle biopsies at rest and 30 min after exercise. We found that 216 mRNAs corresponding to 130 genes changed significantly after exercise. Transcriptional regulators were significantly over-represented. Analysis of the 5' untranslated regions of the affected genes showed significant enrichment in transcription factor response elements, including motifs for NFKB1, RELA, SP1/KLF family, and EGR1. Analysis of the 5' UTR of these transcription factors revealed one common potential transcriptional regulator, myeloid zinc finger 1 (MZF1). The change in MZF1 expression after exercise was positively correlated with insulin sensitivity. MZF1 expression also was increased markedly in insulin resistant obese and diabetic patients, suggesting dysregulation of this system. We used these experiments to conduct a closer examination of more factors that regulate mRNA and protein abundance. Among these, microRNAs (miRNAs) regulate much of gene expression and translation events. Preliminary Data shows that, in healthy people, exercise increases microRNAs that target FOXO1 mRNA, and FOXO1 protein is increased in obese and type 2 diabetic muscle, accompanied by decreased FOXO1 phosphorylation, indicating potential activation of the FOXO1 transcriptional program in insulin resistant muscle. There are few data on how exercise and insulin sensitivity interact in skeletal muscle with regard to global miRNA expression events in human muscle. Finally, the expression of PPARα and its downstream targets decreased 30 minutes after acute exercise in an insulin sensitivity-related manner. In mice PPARα overexpression in muscle worsens and PPARα knockout improves insulin sensitivity. Thus, PPARα activation in muscle may detrimental to insulin sensitivity, and begs the question of whether treatment with fibrates to lower plasma lipids could work against insulin sensitizing effects of exercise in skeletal muscle. The overall goal of this project is to understand the interplay between insulin sensitivity and the gene expression response to exercise in skeletal muscle. Although substantial data is available in mice and in vitro systems, the applicability of these data to human disease is required. We propose: 1. To determine whether the transcription factor expression response to exercise is dysregulated in muscle from type 2 diabetic patients; 2. To determine how insulin resistance changes the response of posttranslational modifications of SP1/KLF family and MZF1 transcription factors to acute exercise in muscle from type 2 diabetic patients; 3. To define the response of miRNAs to acute exercise in healthy and insulin resistant muscle from obese and type 2 diabetic patients; 4. To determine whether treatment with PPARα agonist fibrate derivatives suppresses the normal gene expression response to acute exercise.