Skeletal Muscle Fiber-type Switching, Exercise Intolerance, and Myopathy in PGC-1α Muscle-specific Knock-out Animals

TLDR

PGC‑1α is a key integrator of neuromuscular activity that, when overexpressed, increases mitochondrial content and oxidative, fatigue‑resistant fibers, yet whole‑body knock‑outs show no obvious skeletal muscle phenotype. We aimed to determine the specific role of PGC‑1α in skeletal muscle by generating muscle‑specific knock‑out mice. The study examined muscle‑specific PGC‑1α knock‑out mice to assess their muscle function. Muscle‑specific PGC‑1α knock‑outs shift from oxidative type I/IIa fibers to type IIx/IIb, exhibit reduced endurance, fiber damage, and heightened inflammation after treadmill running, underscoring PGC‑1α’s essential role in maintaining fiber type composition and integrity during exertion.

Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a key integrator of neuromuscular activity in skeletal muscle. Ectopic expression of PGC-1alpha in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue-resistant muscle fibers. Whole body PGC-1alpha knock-out mice have a very complex phenotype but do not have a marked skeletal muscle phenotype. We thus analyzed skeletal muscle-specific PGC-1alpha knock-out mice to identify a specific role for PGC-1alpha in skeletal muscle function. These mice exhibit a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal muscle-specific PGC-1alpha knock-out animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running. Our data demonstrate a critical role for PGC-1alpha in maintenance of normal fiber type composition and of muscle fiber integrity following exertion.