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

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 ␤-guanidinopropionic acid (GPA), a creatine analog, which led to similar reductions in the intramuscular ATP͞AMP 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 ␥ coactivator 1␣ and calcium͞calmodulin-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.␤-guanidinopropionic acid ͉ calcium͞calmodulin-dependent protein kinase IV ͉ peroxisome proliferator-activated ␥ receptor coactivator-1␣ ͉ AMP-activated protein kinase

Mitochondrial biogenesis: Which part of “NO” do we understand?

“…(12) In addition, several signal transduction pathways that regulate PGC1a expression independent of changes in intracellular cGMP levels have also been described. (2,6,7,13) Do the data in the present experiments support the contention that the observed NO effects on PGC1a expression are transduced exclusively through a sGC-sensitive, cGMP-dependent signaling pathway? Some insight into this question comes from their studies on the human monocytic cell line U937.…”

“…Signal transduction pathways that modulate mitochondrial biogenesis through the control of PGC1a expression in mammalian tissues. (1,2,4,6,7,13,23) Changes in the levels or ratio of metabolic indices [blue boxes] are sensed by specific protein-modifying enzymes (i.e., kinases, phosphatases). These proteins in turn activate diverse signaling cascades [gold circles] that ultimately affect the expression of PGC1a [pink oval].…”

“…(5) Despite significant advances in our understanding of the role of transcription factors and co-activators in mediating the transcriptional control of respiratory gene expression, the mechanisms by which the expression of these proteins is in turn regulated remain largely unknown. Investigations of the control of mitochondrial biogenesis in the skeletal muscle of transgenic mice have demonstrated that increases in PGC1a levels and mitochondrial content are dependent on the activity of at least two proteins, CaMKIV (6) and AMP kinase, (7) which are regulated by changes in intracellular calcium concentrations and the ATP:AMP ratio, respectively. Thus, an attractive hypothesis is that the expression and activity of PGC1a and other determinants of mitochondrial content are controlled by effector proteins that are capable of monitoring changes in intracellular energy metabolism by virtue of their sensitivity to metabolic activity.…”

Role of 5′AMP-activated protein kinase in skeletal muscle

“…It is believed that PGC-1a is a key protein involved in induction of mitochondrial biogenesis 46 and that functional AMPK is required for PGC-1a gene expression. 44 However, when a2-AMPK KO mice are exercised at moderate intensity for 1.5 h on a treadmill, the transcriptional activity from the PGC-1a gene and PGC-1a mRNA during and into the recovery was not different between wild-type and KO animals despite an B60% reduction in AMPK signalling during rest and exercise. 30 Thus, transcriptional regulation during exercise from the PGC-1a gene can occur without a2-AMPK present and may rely on other factors of which Ca 2 þ may be one of them.…”

“…[41][42][43] Indeed, in transgenic mice expressing a kinase dead a2-AMPK subunit in skeletal muscle, chronic b-guanadinopropionic acid-induced increase in mitochondrial biogenesis was totally abolished 44 and in whole-body a2-AMPK KO mice, chronic AICAR treatment did not result in any increased content of mitochondrial marker proteins in skeletal muscle. 45 Peroxisome proliferator-activated receptor g co-activator-1a (PGC1a) is a co-activator of certain transcription factors and is expressed in skeletal muscle.…”