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P300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle.

ABSTRACT: The Forkhead Box O (FOXO) transcription factors regulate diverse cellular processes, and in skeletal muscle are both necessary and sufficient for muscle atrophy. Although the regulation of FOXO by Akt is well evidenced in skeletal muscle, the current study demonstrates that FOXO is also regulated in muscle via the histone acetyltransferase (HAT) activities of p300/CREB-binding protein (CBP). Transfection of rat soleus muscle with a dominant-negative p300, which lacks HAT activity and inhibits endogenous p300 HAT activity, increased FOXO reporter activity and induced transcription from the promoter of a bona fide FOXO target gene, atrogin-1. Conversely, increased HAT activity via transfection of either wild-type (WT) p300 or WT CBP repressed FOXO activation in vivo in response to muscle disuse, and in C2C12 cells in response to dexamethasone and acute starvation. Importantly, manipulation of HAT activity differentially regulated the expression of various FOXO target genes. Cotransfection of FOXO1, FOXO3a, or FOXO4 with the p300 constructs further identified p300 HAT activity to also differentially regulate the activity of the FOXO homologues. Markedly, decreased HAT activity strongly increased FOXO3a transcriptional activity, while increased HAT activity repressed FOXO3a activity and prevented its nuclear localization in response to nutrient deprivation. In contrast, p300 increased FOXO1 nuclear localization. In summary, this study provides the first evidence to support the acetyltransferase activities of p300/CBP in regulating FOXO signaling in skeletal muscle and suggests that acetylation may be an important mechanism to differentially regulate the FOXO homologues and dictate which FOXO target genes are activated in response to varying atrophic stimuli.

SUBMITTER: Senf SM

PROVIDER: S-EPMC3118617 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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p300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle.

Senf Sarah M SM Sandesara Pooja B PB Reed Sarah A SA Judge Andrew R AR

American journal of physiology. Cell physiology 20110309 6

The Forkhead Box O (FOXO) transcription factors regulate diverse cellular processes, and in skeletal muscle are both necessary and sufficient for muscle atrophy. Although the regulation of FOXO by Akt is well evidenced in skeletal muscle, the current study demonstrates that FOXO is also regulated in muscle via the histone acetyltransferase (HAT) activities of p300/CREB-binding protein (CBP). Transfection of rat soleus muscle with a dominant-negative p300, which lacks HAT activity and inhibits en ...[more]

PMID: 21389279

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Project description:Background: Amino acids, especially leucine, are particularly effective in promoting protein synthesis. Leucine is known to increase the rate of protein synthesis in skeletal muscle through the mechanistic target of rapamycin complex 1-dependent, as well as -independent, signaling pathways. However, the overall translation program is poorly defined, and it is unknown how the activation of these pathways differentially controls the translation of specific mRNAs.Objective: Ribosome profiling and RNA sequencing were used to precisely define the translational program activated by an acute oral dose of leucine.Methods: Adult male C57BL/6 mice were deprived of food overnight before the delivery of an acute dose of l-leucine (9.4 mg) (n = 6) or vehicle (n = 5) and tissues collected 30 min later. Ribosome footprints and total RNA were isolated and subjected to deep sequencing. Changes in gene-specific mRNA abundance and ribosome occupancy were determined between the leucine-treated and control groups by aligning sequence reads to Reference Sequence database mRNAs and applying statistical features of the Bioconductor package edgeR.Results: Our data revealed mRNA features that confer translational control of skeletal muscle mRNAs in response to an acute dose of leucine. The subset of skeletal muscle mRNAs that are activated consists largely of terminal oligopyrimidine mRNAs (false discovery rate: <0.05), whereas those with reduced translation had 5' untranslated regions with increased length. Only the small nuclear RNAs, which are required for ribosome biogenesis, were significantly altered in RNA abundance. The inferred functional translational program activated by dietary leucine includes increased protein synthesis capacity and energy metabolism, upregulation of sarcomere-binding proteins, modulation of circadian rhythm, and suppression of select immune components.Conclusions: These results clarify the translation program acutely stimulated by leucine in mouse skeletal muscle and establish new methodologies for use in future studies of skeletal muscle disease or aging and further examination of downstream effects of leucine on gene expression.

Project description:BACKGROUNDAt the onset of exercise, the speed at which phosphocreatine (PCr) decreases toward a new steady state (PCr on-kinetics) reflects the readiness to activate mitochondrial ATP synthesis, which is secondary to Acetyl-CoA availability in skeletal muscle. We hypothesized that PCr on-kinetics are slower in metabolically compromised and older individuals and are associated with low carnitine acetyltransferase (CrAT) protein activity and compromised physical function.METHODSWe applied 31P-magnetic resonance spectroscopy (31P-MRS) to assess PCr on-kinetics in 2 cohorts of volunteers. Cohort 1 included patients who had type 2 diabetes, were obese, were lean trained (VO2max > 55 mL/kg/min), and were lean untrained (VO2max < 45 mL/kg/min). Cohort 2 included young (20-30 years) and older (65-80 years) individuals with normal physical activity and older, trained individuals. Previous results of CrAT protein activity and acetylcarnitine content in muscle tissue were used to explore the underlying mechanisms of PCr on-kinetics, along with various markers of physical function.RESULTSPCr on-kinetics were significantly slower in metabolically compromised and older individuals (indicating mitochondrial inertia) as compared with young and older trained volunteers, regardless of in vivo skeletal muscle oxidative capacity (P < 0.001). Mitochondrial inertia correlated with reduced CrAT protein activity, low acetylcarnitine content, and functional outcomes (P < 0.001).CONCLUSIONPCr on-kinetics are significantly slower in metabolically compromised and older individuals with normal physical activity compared with young and older trained individuals, regardless of in vivo skeletal muscle oxidative capacity, indicating greater mitochondrial inertia. Thus, PCr on-kinetics are a currently unexplored signature of skeletal muscle mitochondrial metabolism, tightly linked to functional outcomes. Skeletal muscle mitochondrial inertia might emerge as a target of intervention to improve physical function.TRIAL REGISTRATIONNCT01298375 and NCT03666013 (clinicaltrials.gov).FUNDINGRM and MH received an EFSD/Lilly grant from the European Foundation for the Study of Diabetes (EFSD). VS was supported by an ERC starting grant (grant 759161) "MRS in Diabetes."

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P300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle.

Publications

p300 Acetyltransferase activity differentially regulates the localization and activity of the FOXO homologues in skeletal muscle.

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