Overexpression of peroxisome proliferator-activated receptor gamma co-activator-1alpha leads to muscle atrophy with depletion of ATP.

Abstract

Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) is a key nuclear receptor co-activator for mitochondrial biogenesis. Here we report that overexpression of PGC-1alpha in skeletal muscles increased mitochondrial number and caused atrophy of skeletal muscle, especially type 2B fiber-rich muscles (gastrocnemius, quadriceps, and plantaris). Muscle atrophy became evident at 25 weeks of age, and a portion of the muscle was replaced by adipocytes. Mice showed increased energy expenditure and reduced body weight; thyroid hormone levels were normal. Mitochondria exhibited normal respiratory chain activity per mitochondrion; however, mitochondrial respiration was not inhibited by an ATP synthase inhibitor, oligomycin, clearly indicating that oxidative phosphorylation was uncoupled. Accordingly, ATP content in gastrocnemius was markedly reduced. A similar phenotype is observed in Luft's disease, a mitochondrial disorder that involves increased uncoupling of respiration and muscle atrophy. Our results indicate that overexpression of PGC-1alpha in skeletal muscle increases not only mitochondrial biogenesis but also uncoupling of respiration, resulting in muscle atrophy.

• Authors: Shinji Miura, Eriko Tomitsuka, Yasutomi Kamei, Tomomi Yamazaki, Yuko Kai, Mayumi Tamura, Kiyoshi Kita, Ichizo Nishino, Osamu Ezaki
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 4 Pg. 1129-39 (Oct 2006) ISSN: 0002-9440 [Print] United States
• PMID: 17003473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Trans-Activators
• Transcription Factors
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (deficiency)
• Adipocytes (pathology)
• Animals
• Body Weight (genetics)
• Cell Proliferation
• Cell Respiration
• Female
• Male
• Mice
• Mice, Transgenic
• Mitochondria, Muscle (metabolism, ultrastructure)
• Muscle, Skeletal (metabolism, ultrastructure)
• Muscular Atrophy (genetics, pathology)
• Oxidative Phosphorylation
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Trans-Activators (genetics)
• Transcription Factors
• Transcriptional Activation