Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease.
AMP-Activated Protein Kinase Kinases
/ metabolism
Animals
Female
Homeostasis
Humans
Immunoprecipitation
Liver Diseases, Alcoholic
/ complications
Male
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Myoblasts
/ metabolism
Protein Phosphatase 2
/ metabolism
Sarcopenia
/ etiology
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
revised:
09
07
2020
received:
20
02
2020
accepted:
29
07
2020
pubmed:
18
8
2020
medline:
6
1
2022
entrez:
18
8
2020
Statut:
ppublish
Résumé
Despite the high clinical significance of sarcopenia in alcohol-associated cirrhosis, there are currently no effective therapies because the underlying mechanisms are poorly understood. We determined the mechanisms of ethanol-induced impaired phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine monophosphate-activated protein kinase (AMPK) with consequent dysregulated skeletal muscle protein homeostasis (balance between protein synthesis and breakdown). Differentiated murine myotubes, gastrocnemius muscle from mice with loss and gain of function of regulatory genes following ethanol treatment, and skeletal muscle from patients with alcohol-associated cirrhosis were used. Ethanol increases skeletal muscle autophagy by dephosphorylating mTORC1, circumventing the classical kinase regulation by protein kinase B (Akt). Concurrently and paradoxically, ethanol exposure results in dephosphorylation and inhibition of AMPK, an activator of autophagy and inhibitor of mTORC1 signaling. However, AMPK remains inactive with ethanol exposure despite lower cellular and tissue adenosine triphosphate, indicating a "pseudofed" state. We identified protein phosphatase (PP) 2A as a key mediator of ethanol-induced signaling and functional perturbations using loss and gain of function studies. Ethanol impairs binding of endogenous inhibitor of PP2A to PP2A, resulting in methylation and targeting of PP2A to cause dephosphorylation of mTORC1 and AMPK. Activity of phosphoinositide 3-kinase-γ (PI3Kγ), a negative regulator of PP2A, was decreased in response to ethanol. Ethanol-induced molecular and phenotypic perturbations in wild-type mice were observed in PI3Kγ Our study describes the mechanistic underpinnings for ethanol-mediated dysregulation of protein homeostasis by PP2A that leads to sarcopenia with a potential for therapeutic approaches by targeting the PI3Kγ-PP2A axis.
Sections du résumé
BACKGROUND AND AIMS
Despite the high clinical significance of sarcopenia in alcohol-associated cirrhosis, there are currently no effective therapies because the underlying mechanisms are poorly understood. We determined the mechanisms of ethanol-induced impaired phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine monophosphate-activated protein kinase (AMPK) with consequent dysregulated skeletal muscle protein homeostasis (balance between protein synthesis and breakdown).
APPROACH AND RESULTS
Differentiated murine myotubes, gastrocnemius muscle from mice with loss and gain of function of regulatory genes following ethanol treatment, and skeletal muscle from patients with alcohol-associated cirrhosis were used. Ethanol increases skeletal muscle autophagy by dephosphorylating mTORC1, circumventing the classical kinase regulation by protein kinase B (Akt). Concurrently and paradoxically, ethanol exposure results in dephosphorylation and inhibition of AMPK, an activator of autophagy and inhibitor of mTORC1 signaling. However, AMPK remains inactive with ethanol exposure despite lower cellular and tissue adenosine triphosphate, indicating a "pseudofed" state. We identified protein phosphatase (PP) 2A as a key mediator of ethanol-induced signaling and functional perturbations using loss and gain of function studies. Ethanol impairs binding of endogenous inhibitor of PP2A to PP2A, resulting in methylation and targeting of PP2A to cause dephosphorylation of mTORC1 and AMPK. Activity of phosphoinositide 3-kinase-γ (PI3Kγ), a negative regulator of PP2A, was decreased in response to ethanol. Ethanol-induced molecular and phenotypic perturbations in wild-type mice were observed in PI3Kγ
CONCLUSIONS
Our study describes the mechanistic underpinnings for ethanol-mediated dysregulation of protein homeostasis by PP2A that leads to sarcopenia with a potential for therapeutic approaches by targeting the PI3Kγ-PP2A axis.
Identifiants
pubmed: 32799332
doi: 10.1002/hep.31524
pmc: PMC8847884
mid: NIHMS1775621
doi:
Substances chimiques
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
Protein Phosphatase 2
EC 3.1.3.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1892-1908Subventions
Organisme : NHLBI NIH HHS
ID : R56 HL141744
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK061732
Pays : United States
Organisme : NIAAA NIH HHS
ID : R00 AA025386
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK083251
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA028190
Pays : United States
Organisme : NIAAA NIH HHS
ID : R21 AA022742
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA026976
Pays : United States
Organisme : NIAAA NIH HHS
ID : K08 AA028794
Pays : United States
Organisme : NIAAA NIH HHS
ID : L30 AA027927
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113196
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA024333
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM119174
Pays : United States
Organisme : NIAMS NIH HHS
ID : R21 AR071046
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL089473
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK083414
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA021890
Pays : United States
Informations de copyright
© 2020 by the American Association for the Study of Liver Diseases.
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