Understanding the acetylome: translating targeted proteomics into meaningful physiology

Abstract

It is well established that exercise elicits a finely tuned adaptive response in skeletal muscle, with contraction frequency, duration, and recovery shaping skeletal muscle plasticity. Given the power of physical activity to regulate metabolic health, numerous research groups have focused on the molecular mechanisms that sense, interpret, and translate this contractile signal into postexercise adaptation. While our current understanding is that contraction-sensitive allosteric factors (e.g., Ca2+, AMP, NAD+, and acetyl-CoA) initiate signaling changes, how the muscle translates changes in these factors into the appropriate adaptive response remains poorly understood. During the past decade, systems biology approaches, utilizing “omics” screening techniques, have allowed researchers to define global processes of regulation with incredible sensitivity and specificity. As a result, physiologists are now able to study substrate flux with stable isotope tracers in combination with metabolomic approaches and to coordinate these functional changes with proteomic and transcriptomic analysis. In this review, we highlight lysine acetylation as an important posttranslational modification in skeletal muscle. We discuss the evolution of acetylation research and detail how large proteomic screens in diverse metabolic systems have led to the current hypothesis that acetylation may be a fundamental mechanism to fine-tune metabolic adaptation in skeletal muscle.

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

“…However, we observed that Sirt2 inhibition did not diminish piericidin-A-and antimycin-A-induced AMPK phosphorylation, suggesting that Sirt2 operates downstream of AMPK. A large number of glycolytic enzymes can be acetylated, and reversible acetylation is believed to fine-tune metabolic adaptation and insulin signaling in muscle (LaBarge et al, 2015;Philp et al, 2014). We here observed that the Glut1 acetylation status was similar under basal and OXPHOS-inhibited conditions, suggesting that Glut1 is not directly modulated by acetylation and/or is not a direct target of Sirt2.…”

Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase

“…4 In total, the mammalian acetylome comprises over 3600 lysine acetylation sites that regulate myriad cellular functions. 5,6 …”

p300 is not required for metabolic adaptation to endurance exercise training

“…The acetylation state of a protein is balanced between the activity of deacetylases (DACs) and lysine acetyltransferases (KATs), which remove and add an acetyl group to lysine residues, respectively (1)(2)(3). In recent years, research has focused almost exclusively on the action of DACs in regulating protein acetylation, muscle metabolism, and mitochondrial biogenesis, with the majority of studies focusing on the sirtuin (SIRT) proteins: SIRT1 and SIRT3 (4)(5)(6)(7). Remarkably, little is known about how KATs modulate these processes, particularly in vivo.…”