MUSCLE SPECIFIC OVEREXPRESSION OF PGC-1α1 PROMOTES FAVORABLE EXERCISE RESPONSES UNDER LIPID OVERLOAD CONDITIONS REGARDLESS OF EXERCISE VOLUME

Megan E. Rosa-Caldwell1, Jacob L. Brown1, David E. Lee1, Thomas A. Blackwell1, Richard A. Perry Jr.1, Wesley S. Haynie1, Lemuel A. Brown1, Tyrone A. Washington1, Nicholas P. Greene1 1University of Arkansas Obesity and its associated comorbidities remain the pivotal public health concern of the 21st century. One predominant interest in the development of insulin resistance is the degradation and dysfunction of skeletal mitochondria. PGC-1α1, the principle regulator of mitochondrial biogenesis has been proposed as a possible therapeutic target to alleviate lipid overload-induced mitochondrial dysfunction, yet current data remain controversial on the efficacy of artificially promoting PGC-1α1 as a therapeutic modality. PURPOSE: The purpose of this study was to investigate the efficacy of genetic overexpression of PGC-1α1 alone and in combination with physical activity as a therapeutic agent during lipid overload. METHODS: ~40 wild type (WT) mice and mice with muscle-specific overexpression of PGC-1α1 (MCK-PGC-1α) were given Western Diet (WD) at 8 wks of age and allowed to consume food ab libitum throughout the course of the study. At 12 wks of age, animals were randomly divided into sedentary (SED) and physical activity (voluntary wheel running [VWR]) interventions. At ages 7, 11, and 15 wks animals underwent glucose tolerance tests (GTT). At 16 wks of age animals were humanly euthanized and tissues collected for analysis. RESULTS: MCK-PGC-1α animals were slightly lighter and had less epididymal fat compared to WT (~6% and ~28% respectively). Food efficiency (ratio of weight gained to food consumed) was ~17% lower in MCK-PGC-1α animals. While there was no difference at 7 wks age, at 11 wks age MCK-PGC-1α had ~50% greater integrated area under the curve (IAUC) compared to WT. Yet at 15 wks, VWR had 30% lower IAUC compared to SED, regardless of genotype. MCK-PGC-1α -VWR ran ~3X more per day compared to WT-VWR. Correlations for distance per day v. IAUC, body weight, and epididymal fat were significant and moderately strong (r=-0.67--0.71) for WT-VWR, but in TG there was no correlation between these variables and distance per day (r=0.10-0.20). CONCLUSION: Taken together, these results suggest increasing PGC-1α1 may augment exercise-induced adaptations regardless of exercise volume, but overexpression of PGC-1α1 during lipid overload without physical activity does not appear to mitigate insulin resistance and may in fact exacerbate the condition