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  • When skeletal muscle ages there


    When skeletal muscle ages, there is an increase in frailty, which is coincident with a decrease in muscle mass and function—this condition is called sarcopenia (Cruz-Jentoft et al., 2010). It has been shown that one of the major pathways downregulated at the onset of sarcopenia is the mitochondrial pathway, such as those genes involved in OXPHOS and the TCA cycle (Ibebunjo et al., 2013, Marzetti et al., 2013). A decline in concentrations of circulating IGF1 in sarcopenia has been described in humans and rodents (O’Connor et al., 1998, Velasco et al., 1998). This study suggests the possibility that re-activation of ACL in settings of sarcopenia might be helpful in restoring mitochondrial competence. Of interest, in this study it was observed that phosphorylated ACL is dramatically reduced in old (24 months) versus young mice, coincident with a decrease in levels of AKT phosphorylation with age. Therefore, the goal would be to reactivate ACL in settings of sarcopenia, perhaps by restoring IGF1 signaling to physiologic levels in this setting. It remains to be seen whether genetic manipulation of ACL in old mice affects mitochondrial and skeletal muscle function. Homozygous ACL knockout mice die early in development (Beigneux et al., 2004); therefore, the generation of a skeletal muscle-specific knockout, or perhaps transgenic mice expressing activated ACL, would be needed to address this question.
    Experimental Procedures
    Author Contributions
    Introduction Acetyl-coenzyme A (CoA) is a central molecule in cell metabolism, signaling, and epigenetics. It serves crucial roles in energy production, macromolecular biosynthesis, and protein modification (Carrer and Wellen, 2015, Pietrocola et al., 2015). Within mitochondria, acetyl-CoA is generated from pyruvate by the pyruvate dehydrogenase complex (PDC), as well as from catabolism of fatty acids and amino acids. To enter the tricarboxylic cyclic adenosine monophosphate (TCA) cycle, acetyl-CoA condenses with oxaloacetate, producing citrate, a reaction catalyzed by citrate synthase. Transfer of acetyl-CoA from mitochondria to the cytosol and nucleus involves the export of citrate and its subsequent cleavage by ATP-citrate lyase (ACLY), generating acetyl-CoA and oxaloacetate. This acetyl-CoA is used for a number of important metabolic functions, including synthesis of fatty acids, cholesterol, and nucleotide sugars such as UDP-N-acetylglucosamine. Acetyl-CoA also serves as the acetyl-group donor for both lysine and N-terminal acetylation (Carrer and Wellen, 2015, Pietrocola et al., 2015). ACLY plays an important role in regulating histone acetylation levels in diverse mammalian cell types (Covarrubias et al., 2016, Donohoe et al., 2012, Lee et al., 2014, Wellen et al., 2009). In addition to ACLY, nuclear-cytosolic acetyl-CoA is produced from acetate by acyl-CoA synthetase short chain family member 2 (ACSS2) (Luong et al., 2000). Recent studies have revealed an important role for this enzyme in hypoxia and in some cancers (Comerford et al., 2014, Gao et al., 2016, Kamphorst et al., 2014, Mashimo et al., 2014, Schug et al., 2015, Schug et al., 2016, Yoshii et al., 2009). Acetate can be produced intracellularly by histone deacetylase reactions or can be imported from the environment (Carrer and Wellen, 2015). Levels of acetate in circulating blood are rather low, ranging from 50 to 200 μM in humans, although acetate concentrations can increase substantially in certain conditions, such as following alcohol consumption, high-fat feeding, or infection, or in specific locations such as the portal vein (Balmer et al., 2016, Herrmann et al., 1985, Lundquist et al., 1962, Perry et al., 2016, Scheppach et al., 1991, Skutches et al., 1979, Tollinger et al., 1979). Acetate is also exported by cells under certain conditions, such as low intracellular pH (McBrian et al., 2013), and thus could potentially be made available for uptake by other cells in the immediate microenvironment. Two additional acetyl-CoA-producing enzymes, the PDC and carnitine acetyltransferase (CrAT), have been reported to be present in the nucleus and to contribute acetyl-CoA for histone acetylation (Madiraju et al., 2009, Sutendra et al., 2014). The PDC was shown to translocate from mitochondria to the nucleus under certain conditions, such as growth factor stimulation; within the nucleus, the complex is intact and retains the ability to convert pyruvate to acetyl-CoA (Sutendra et al., 2014). The relative contributions of each of these enzymes to the regulation of histone acetylation and lipid synthesis, as well as the mechanisms of metabolic flexibility between these enzymes, are poorly understood.