Adult Deletion of PGC-1α and β in Skeletal Muscle Improves Glucose Tolerance Despite the Development of Mitochondrial Dysfunction
Presentation Number: LB MON 79
Date of Presentation: April 3rd, 2017
Zachary Bush1, Christopher Ballmann2, Yawen Tang1, Martin E. Young1 and Glenn C. Rowe*1
1University of Alabama at Birmingham, Birmingham, AL, 2University of Alabama at Birmingham
Skeletal muscle mitochondrial dysfunction has been proposed as a major contributor to insulin resistance and ultimately the development of type II diabetes (T2D). Interventions, such as exercise, which are able to improve mitochondrial function have been shown to be a powerful tool in both the prevention and reversal of T2D. The peroxisome proliferator-activated receptor gamma, coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as potent regulators of mitochondrial function, energy homeostasis and whole body metabolism. Moreover, dysregulation of PGC-1s has been associated with the onset of metabolic diseases in rodents and humans including obesity and T2D. However, many of these rodent studies utilized either whole body or from birth deletions of PGC-1α and/or PGC-1β. Therefore, we sought to determine whether loss of PGC-1s in adult skeletal muscle would contribute to the development of type II diabetes and insulin resistance, through utilization of an inducible muscle-specific deletion of PGC-1α and β (iMyo-PGC-1DKO). We have recently reported that the iMyo-PGC-1DKO animals develop mitochondrial dysfunction (with a marked reduction in electron transport activity) within 4 weeks post-deletion. Consistent with this, ex vivo analysis of substrate utilization revealed that these muscles exhibited impaired glucose and fatty-acid oxidation. in addition, insulin was unable to influence glucose and fatty-acid oxidation ex vivo, suggesting impaired insulin response. Notably the deletion of both PGC-1α and β did not affect fiber composition or muscle strength in the iMyo-PGC-1DKOs, suggesting that observed differences in oxidative metabolism were independent of fibertype. Surprisingly, deletion of both PGC-1s resulted in increased glucose clearance from circulation determined by glucose tolerance test (GTT), with no difference in insulin action determined by insulin tolerance test (ITT). Taken together these data suggests that although loss of PGC-1s in skeletal muscle adversely affects muscle metabolism, it is not the primary cause of T2D development.
Nothing to Disclose: ZB, CB, YT, MEY, GCR