AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation

TLDR

Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, yet the signaling mechanisms responsible for this response are poorly understood. The study examined whether AMP‑activated protein kinase (AMPK) regulates mitochondrial biogenesis by using transgenic mice expressing a dominant‑negative AMPK mutant in muscle. Transgenic and wild‑type mice were treated with β‑guanidinopropionic acid (GPA), a creatine analog that lowered intramuscular ATP/AMP ratio and phosphocreatine levels, allowing comparison of AMPK activity and mitochondrial responses. GPA activated AMPK and induced mitochondrial biogenesis in wild‑type mice, but had no effect in DN‑AMPK mice, and AMPK inactivation blocked GPA‑induced upregulation of PGC‑1α and CaMKIV, demonstrating that AMPK sensing of energy status is essential for initiating mitochondrial biogenesis.

Abstract

Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, yet the signaling mechanisms responsible for this response are poorly understood. To examine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved fuel sensor, in mitochondrial biogenesis we studied transgenic mice expressing a dominant-negative mutant of AMPK in muscle (DN-AMPK). Both DN-AMPK and WT mice were treated with β-guanidinopropionic acid (GPA), a creatine analog, which led to similar reductions in the intramuscular ATP/AMP ratio and phosphocreatine concentrations. In WT mice, GPA treatment resulted in activation of muscle AMPK and mitochondrial biogenesis. However, the same GPA treatment in DN-AMPK mice had no effect on AMPK activity or mitochondrial content. Furthermore, AMPK inactivation abrogated GPA-induced increases in the expression of peroxisome proliferator-activated receptor γ coactivator 1α and calcium/calmodulin-dependent protein kinase IV (both master regulators of mitochondrial biogenesis). These data demonstrate that by sensing the energy status of the muscle cell, AMPK is a critical regulator involved in initiating mitochondrial biogenesis.