ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle

Area of Science:

• Molecular Biology
• Metabolic Regulation
• Exercise Physiology

Background:

• PGC1α is a key regulator of mitochondrial biogenesis, angiogenesis, and muscle remodeling.
• PGC1α interacts with various transcription factors, notably the nuclear receptor ERRγ.
• The precise epistatic relationship between PGC1α/β and ERRγ in muscle remains to be fully elucidated.

Purpose of the Study:

• To investigate the functional consequences of ERRγ gain of function in mice lacking both PGC1α and PGC1β.
• To determine if ERRγ can independently rescue muscle phenotypes associated with PGC1α/β deficiency.
• To explore the combined effects of ERRγ activation and exercise on muscle energy metabolism and performance.

Main Methods:

• Generation of muscle-specific PGC1α/β double-knockout (PKO) mice.
• Induction of ERRγ gain of function in PKO mice.
• Assessment of muscle damage, fiber type, mitochondrial biogenesis, antioxidant capacity, and angiogenesis.
• Evaluation of exercise performance and mitochondrial energetic status.

Main Results:

• ERRγ gain of function significantly rescued muscle damage and improved muscle function in PKO mice.
• ERRγ activation induced mitochondrial biogenesis, antioxidant defense, and angiogenesis independently of PGC1α/β.
• Combined ERRγ activation and voluntary exercise restored mitochondrial energetics and increased running performance fivefold in PKO mice.
• ERRγ-driven transcriptional reprogramming promoted a glycolytic-to-oxidative fiber-type transformation.

Conclusions:

• Estrogen-related receptors (ERRs) act as major molecular targets for PGC1α/β in regulating muscle energy metabolism.
• ERRγ gain of function can largely compensate for the loss of PGC1α/β in muscle.
• These findings reveal a critical role for ERRs in mediating both innate and adaptive responses to metabolic challenges in skeletal muscle.