Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 25, Pages 15983-15987Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.252625599
Keywords
beta-guanidinopropionic acid; calcium/calmodulin-dependent protein kinase IV; peroxisome proliferator-activated gamma receptor coactivator-1 alpha; AMP-activated protein kinase
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Funding
- NHLBI NIH HHS [R01 HL-6381] Funding Source: Medline
- NIDDK NIH HHS [R01 DK040936, R01 DK-40936, U24 DK-59635, P30 DK045735, P30 DK-45735, U24 DK059635] Funding Source: Medline
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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 beta-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 gamma coactivator 1alpha 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.
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