The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 10 No.
3 • November 2007
Practical Do-It-Yourself Information
Importance of PGC-1alpha in Maintaining Skeletal Muscle Function and Integrity
Many of the discoveries about mechanisms of aging cannot be utilized at present, either because the technology for doing so is not developed or because not enough is known about the biochemical pathways involved to be able to safely modify them. For example, a great deal is now known about how to increase the lifespan of fruit flies, nematodes, and rodents by adding or removing or altering the activity of various genes. None of this is of much use to humans trying to increase their lifespan at present. It is the information that we can actually use that we prefer to emphasize in this newsletter. As we have reported earlier, evidence exists that supports the possibility of increasing PGC-1alpha expression through the inhibition of the fat-synthesizing hormone fatty acid synthase by certain types of green and Pu-erh teas (available in our ShapeShifter Teas™).
We have extensively discussed, in an
article in the April 2007 issue of Life Enhancement magazine (pp. 4–6), how inhibiting fatty acid synthase (FAS), the enzyme that carries out the final step in the synthesis of stored body fat, by consuming particular types of tea, results in a significant increase in the expression of PGC-1alpha (the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha). Higher expression of PGC-1alpha, as we explained, results in mitochondrial biogenesis and a higher number of type IIa and type I oxidative, slow-twitch, high-endurance muscle fibers. PGC-1alpha also blunts skeletal muscle atrophy that normally occurs in disuse. This new paper provides powerful additional support for these functions of PGC-1alpha.
In the new paper, researchers created a mouse that had its PGC-1alpha knocked out, but only in its skeletal muscle, so that the effects could be evaluated for skeletal muscle rather than being confounded by the very many effects of PGC-1alpha in other tissues. [Mice with whole-body PGC-1alpha knockout were reported to be hyperactive, had circadian abnormalities, and had constitutively (constantly on) gluconeogenic (glucose-creating) and heme-biosynthetic genes in the liver, even in the fed state.]
The PGC-1alpha-skeletal-muscle knockout mice were found to have moderate reduction in the number of oxidative type I and type IIa muscle fibers and reduced exercise capacity. Their skeletal muscle had a low level of damaged and regenerating muscle fibers, indicating low maintenance capacity. These deficiencies were dramatically increased by physical exercise and accompanied by elevated markers of systemic inflammation. “Our data thus highlight the importance of PGC-1alpha in maintaining proper function and integrity of skeletal muscle.”
As the authors explain, “Different factors could contribute to the muscle pathology in MKOs [muscle-specific PGC-1alpha knockout animals]. First, these animals have a reduction in mitochondrial gene expression. Mitochondrial dysfunction is associated with muscle damage in Duchenne muscular dystrophy. Second, reactive oxygen species detoxification is crucially regulated by PGC-1alpha, and the levels of a number of reactive oxygen species detoxification genes are reduced in MKOs, including superoxide dismutase 1 [CuZn superoxide dismutase], superoxide dismutase 2 [Mn superoxide dismutase], adenine nucleotide transporter, and glutathione peroxidase 1. . . . Finally, systemic inflammation, acute and chronic, is a strong promoter of skeletal muscle wasting.”
- Handschin et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha-specific knock-out animals. J Biol Chem 282(41):30014-21 (2007).