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      ATP citrate lyase improves mitochondrial function in skeletal muscle.

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          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.

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          Author and article information

          Journal
          Cell Metab.
          Cell metabolism
          1932-7420
          1550-4131
          Jun 2 2015
          : 21
          : 6
          Affiliations
          [1 ] Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
          [2 ] Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. Electronic address: david.glass@novartis.com.
          [3 ] Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland. Electronic address: mara.fornaro@novartis.com.
          Article
          S1550-4131(15)00218-1
          10.1016/j.cmet.2015.05.006
          26039450
          2257b1ee-1213-48bd-82d8-b0e8d41f55fb
          Copyright © 2015 Elsevier Inc. All rights reserved.
          History

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