title: ATP citrate lyase improves mitochondrial function in skeletal muscle.
abstract: Mitochondrial dysfunction is associated with skeletal muscle pathology, including cachexia, sarcopenia, and the muscular dystrophies. ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes mitochondria-derived citrate into oxaloacetate and acetyl-CoA. Here we report that activation of ACL in skeletal muscle results in improved mitochondrial function. IGF1 induces activation of ACL in an AKT-dependent fashion. This results in an increase in cardiolipin, thus increasing critical mitochondrial complexes and supercomplex activity, and a resultant increase in oxygen consumption and cellular ATP levels. Conversely, knockdown of ACL in myotubes not only reduces mitochondrial complex I, IV, and V activity but also blocks IGF1-induced increases in oxygen consumption. In vivo, ACL activity is associated with increased ATP. Activation of this IGF1/ACL/cardiolipin pathway combines anabolic signaling with induction of mechanisms needed to provide required ATP.
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Suman
authors.initials: S
authors.lastname: Das
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Morvan
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Jourde
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Viktor
authors.initials: V
authors.lastname: Meier
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Kahle
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Brebbia
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
authors.forename: Gauthier
authors.initials: G
authors.lastname: Toussaint
authors.affiliation: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. Electronic address: david.glass@novartis.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland. Electronic address: mara.fornaro@novartis.com.
authors.forename: Mara
authors.initials: M
authors.lastname: Fornaro
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D019343:Citric Acid / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology*; D010101:Oxygen Consumption / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002308:Cardiolipins; C583557:IGF1 protein, human; D019343:Citric Acid; D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D001275:ATP Citrate (pro-S)-Lyase