PGC-1α Deficiency Causes Multi-System Energy Metabolic Derangements: Muscle Dysfunction, Abnormal Weight Control and Hepatic Steatosis

Teresa C Leone,Brian N Finck,Robert E Schmidt,E Dale Abel,Denis M Medeiros,Zhouji Chen,Daniel P Kelly,Carlos Bernal-Mizrachi,Michael Courtois,John O Holloszy,Nandakumar Sambandam,John J Lehman,Paul J Schaeffer,Sihem Boudina,David F Wozniak,Jeffrey E Saffitz,Clay F Semenkovich,Adam R Wende

doi:10.1371/journal.pbio.0030101

Abstract

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α−/− mice. With age, the PGC-1α−/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

Highlights

Mitochondrial functional capacity is dynamically regulated to meet the diverse energy demands imposed on the mammalian organism following birth
Recent evidence points toward a transcriptional coactivator, peroxisome proliferator-activated receptor-c (PPARc) coactivator-1a (PGC-1a), as an integrator of the molecular regulatory circuitry involved in the transcriptional control of cellular energy metabolism, including mitochondrial function and biogenesis [1,2]
Gain-of-function strategies cannot determine whether PPARc coactivator (PGC)-1a is essential for critical energy metabolic processes including mitochondrial biogenesis and function

Summary

Introduction

Mitochondrial functional capacity is dynamically regulated to meet the diverse energy demands imposed on the mammalian organism following birth. Recent evidence points toward a transcriptional coactivator, peroxisome proliferator-activated receptor-c (PPARc) coactivator-1a (PGC-1a), as an integrator of the molecular regulatory circuitry involved in the transcriptional control of cellular energy metabolism, including mitochondrial function and biogenesis [1,2]. The expression of the gene encoding PGC-1a is rapidly induced by cold exposure, short-term exercise, and fasting [2,8,9,10,11,12,13,14,15].

Methods

Results

Conclusion