Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity

Abstract

SUMMARY Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α−/−βf/f/MLC-Cre mice) were generated and characterized. PGC-1α−/−βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α−/−βf/f/MLC-Cre mice was associated with a marked diminution in muscle respiratory capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α−/−βf/f/MLC-Cre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α−/−βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity.

Sirtuin 1-mediated Effects of Exercise and Resveratrol on Mitochondrial Biogenesis

“…Whether these transient modifications of PGC-1␣ have an impact on RSV-mediated mitochondrial biogenesis remains to be determined. There is also considerable contention as to whether PGC-1␣ acts as a sole regulator of the induction of organelle synthesis in muscle, at least in response to exercise (20,(53)(54)(55). Thus, this raises the possibility that RSV may act through other mediators of mitochondrial biogenesis such as PGC-␤ or PGC-1␣-related coactivator.…”

Mitochondrial Complex I Deficiency Enhances Skeletal Myogenesis but Impairs Insulin Signaling through SIRT1 Inactivation

“…The role of dysfunctional mitochondria in the development of type 2 diabetes has been highly controversial because mitochondrial dysfunction leads to the protection against obesity and insulin resistance in apoptosis-inducing factor 1 (AIF1)-, mitochondrial transcription factor A (TFAM)-, or PGC-1␣/␤-deficient mice (32,33,57). However, our data showed that CI dysfunction resulted in a decrease of the NAD ϩ /NADH ratio, the deactivation of SIRT1, an increased expression level of PTP1B, the inactivation of IR␤ and IRS-1, and insulin resistance (Fig.…”

“…However, this proposal has been challenged because the expression levels of the OXPHOS proteins are similar in the skeletal muscles of lean and db/db mice, and OXPHOS function is similar in diabetic and nondiabetic Asian Indians (28 -30). In addition, disruption of mitochondrial transcription factor A (TFAM), apoptosis-inducing factor, or PGC-1␣ and PGC-1␤␤ improves glucose tolerance and increases insulin sensitivity despite severe CI activity loss and mitochondrial defects (31)(32)(33).…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…Nevertheless, when overexpressed in skeletal muscle, genes involved in oxidative phosphorylation and fatty acid oxidation are also upregulated by PGC-1β resulting structurally in a higher mitochondrial density and functionally in a better endurance performance [89]. Inversely, skeletal muscle-specific PGC-1 deletion causes lower endurance capacity [106]. A combined deficiency of PGC-1 and PGC-1 in a global PGC-1α and a musclespecific PGC-1β knockout background aggravates this phenotype displaying a very severe exercise deficit, strongly reduced oxidative capacity and mitochondrial structure and function derangements.…”