Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin
Christoph Zechner1, Ling Lai, Juliet F Zechner
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Abstract:
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(-/-)β(f/f/MLC-Cre) mice) were generated and characterized. PGC-1α(-/-)β(f/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(-/-)β(f/f/MLC-Cre) mice was associated with a marked diminution in muscle oxidative capacity, together with rapid depletion of muscle glycogen stores. In addition, the PGC-1α/β-deficient muscle exhibited mitochondrial structural derangements consistent with fusion/fission and biogenic defects. Surprisingly, the proportion of oxidative muscle fiber types (I, IIa) was not reduced in the PGC-1α(-/-)β(f/f/MLC-Cre) mice. Moreover, insulin sensitivity and glucose tolerance were not altered in the PGC-1α(-/-)β(f/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.
Insights
Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) coactivators are essential for skeletal muscle oxidative capacity and mitochondrial function. However, they are not required for muscle fiber type determination or insulin sensitivity.
Area of Science:
- Molecular Biology
- Exercise Physiology
- Mitochondrial Biology
Background:
- Peroxisome proliferator-activated receptor gamma coactivators (PGC-1s) are key regulators of cellular energy metabolism.
- Emerging evidence highlights their critical roles in skeletal muscle function, metabolism, and disease.
- The specific contributions of PGC-1α and PGC-1β in skeletal muscle remain incompletely understood.
Purpose of the Study:
- To investigate the necessity of combined PGC-1α and PGC-1β coactivators for skeletal muscle oxidative capacity, exercise performance, and metabolic homeostasis.
- To elucidate the impact of PGC-1α/β deficiency on mitochondrial structure and function in skeletal muscle.
- To determine if PGC-1 coactivators influence muscle fiber type composition and insulin sensitivity.
Main Methods:
- Generation and characterization of mice with complete PGC-1α and PGC-1β deficiency in skeletal muscle (PGC-1α(-/-)β(f/f/MLC-Cre)).
- Assessment of exercise performance, muscle oxidative capacity, and glycogen stores.
- Mitochondrial structural analysis using electron microscopy.
- Evaluation of muscle fiber type proportions, insulin sensitivity, and glucose tolerance.
Main Results:
- PGC-1α(-/-)β(f/f/MLC-Cre) mice displayed significantly reduced exercise performance compared to controls.
- Muscle oxidative capacity was markedly diminished, and glycogen stores were rapidly depleted in deficient mice.
- Mitochondria exhibited structural abnormalities indicative of fusion/fission and biogenic defects.
- Surprisingly, muscle fiber type proportions (oxidative types I and IIa) and insulin sensitivity/glucose tolerance remained unaltered.
Conclusions:
- PGC-1 coactivators are indispensable for maintaining skeletal muscle oxidative programs and mitochondrial integrity.
- Despite their crucial role in mitochondrial function, PGC-1 coactivators are dispensable for determining fundamental muscle fiber types.
- Skeletal muscle PGC-1 coactivators do not appear to be critical regulators of systemic insulin sensitivity or glucose tolerance.
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