Alcohol Intoxication Impairs Phosphorylation of S6K1 and S6 in Skeletal Muscle Independently of Ethanol Metabolism

Lang, Charles H.; Pruznak, Anne M.; Deshpande, Nobuko; Palopoli, Margaret M.; Frost, Robert A.; Vary, Thomas C.

doi:10.1097/01.alc.0000145787.66405.59

Cited by 51 publications

(104 citation statements)

References 20 publications

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“…Age-matched overnight-fed male and female rats were divided randomly into two groups; the alcoholtreated group was injected intraperitoneally with ethanol (75 mmol/kg body wt; 20% wt/vol in saline), and the control group was injected with an equal volume of 0.9% sterile saline. This dose of ethanol was selected because it significantly decreases muscle protein synthesis (15,19,34). The inhibition of muscle protein synthesis is independent of the route of alcohol administration (e.g., ip injection vs. oral gavage; see Ref.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibition of muscle protein synthesis is independent of the route of alcohol administration (e.g., ip injection vs. oral gavage; see Ref. 19). Rats were wrapped loosely in a porous towel at 30, 60, and 90 min, and a small (ϳ0.2 ml) blood sample was collected from a tail snip for determination of alcohol concentration.…”

Section: Methodsmentioning

confidence: 99%

“…Although the etiology of this alcohol myopathy is multifactorial, at least one defect pertains to the diminished synthetic rate of structural and myofibrillar proteins (29,31,42). A decrease in protein synthesis is also observed in fast-twitch muscles in response to acute alcohol intoxication (15,19,34). Alcohol reduces translational efficiency in skeletal muscle by limiting peptide-chain initiation (19,20,37).…”

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confidence: 99%

“…A decrease in protein synthesis is also observed in fast-twitch muscles in response to acute alcohol intoxication (15,19,34). Alcohol reduces translational efficiency in skeletal muscle by limiting peptide-chain initiation (19,20,37). A decreased activity of the prolinedirected serine (Ser)/threonine (Thr) protein kinase mammalian target of rapamycin (mTOR) appears to be a primary locus for this impairment.…”

mentioning

confidence: 99%

“…A decreased activity of the prolinedirected serine (Ser)/threonine (Thr) protein kinase mammalian target of rapamycin (mTOR) appears to be a primary locus for this impairment. This is evidenced by the alcohol-induced dephosphorylation of mTOR per se as well as of two mTOR substrates [the 4E-binding protein (BP)1 and the ribosomal S6 kinase (S6K1] (18,19,42) that control selected aspects of mRNA translation (8).…”

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confidence: 99%

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Skeletal muscle protein synthesis and degradation exhibit sexual dimorphism after chronic alcohol consumption but not acute intoxication

Lang

Frost

Vary

2007

American Journal of Physiology-Endocrinology and Metabolism

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Epidemiological evidence suggests alcoholic myopathy is more severe in females than males, but comparable animal studies are lacking that make elucidating the biochemical locus for this defect problematic. The present study determined whether skeletal muscle protein synthesis and markers of degradation exhibit a sexual dimorphic response to either chronic alcohol consumption or acute intoxication. Male and female rats were fed an alcohol-containing diet, pair-fed for 26 wk (chronic), or received an intraperitoneal injection of alcohol (acute). In males, chronic alcohol decreased gastrocnemius protein synthesis by 20%. This reduction was associated with a twofold increase in the inactive eukaryotic initiation factor (eIF) 4E·4E-binding protein 1 (4E-BP1) complex and a 60% reduction in the active eIF4E·eIF4G complex. This redistribution of eIF4E was associated with decreased phosphorylation of both 4E-BP1 and eIF4G (50–55%). The phosphorylation of ribosomal protein S6 was also reduced 60% in alcohol-consuming male rats. In contrast, neither rates of protein synthesis nor indexes of translation initiation in muscle were altered in alcohol-fed female rats despite blood alcohol levels comparable to males. Chronic alcohol ingestion did not alter atrogin-1 or muscle RING finger-1 mRNA content (biomarkers of muscle proteolysis) in males but increased their expression in females 50–100%. Acute alcohol intoxication produced a comparable decrease in muscle protein synthesis and translation initiation in both male and female rats. Our data demonstrate a sexual dimorphism for muscle protein synthesis, translation initiation, and proteolysis in response to chronic, but not acute, alcohol intoxication; however, they do not support evidence indicating females are more sensitive toward the development of alcoholic skeletal muscle myopathy.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Skeletal muscle protein synthesis and degradation exhibit sexual dimorphism after chronic alcohol consumption but not acute intoxication

Lang

Frost

Vary

2007

American Journal of Physiology-Endocrinology and Metabolism

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The metabolic and molecular mechanisms of hyperammonaemia‐ and hyperethanolaemia‐induced protein catabolism in skeletal muscle cells

Crossland

Smith

Atherton

et al. 2018

Journal Cellular Physiology

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Hyperammonaemia and hyperethanolaemia are thought to be driving factors behind skeletal muscle myopathy in liver disease, that is, cirrhosis. Despite this, the singular and combined impacts of ethanol‐ and ammonia‐induced protein catabolism are poorly defined. As such, we aimed to dissect out the effects of ammonia and ethanol on muscle catabolism. Murine C2C12 myotubes were treated with ammonium acetate (10 mM) and ethanol (100 mM) either alone or in combination for 4 hr and/or 24 hr. Myotube diameter, muscle protein synthesis and anabolic and catabolic signalling pathways were assessed. In separate experiments, cells were cotreated with selected inhibitors of protein breakdown to assess the importance of proteolytic pathways in protein loss with ammonia and ethanol. Ammonia and ethanol in combination resulted in a reduction in myotube width and total protein content, which was greater than the reduction observed with ammonia alone. Both ammonia and ethanol caused reductions in protein synthesis, as assessed by puromycin incorporation. There was also evidence of impairments in regulation of protein translation, and increased protein expression of markers of muscle protein breakdown. Myotube protein loss with ammonia plus ethanol was not affected by autophagy inhibition, but was completely prevented by proteasome inhibition. Thus, combined ammonia and ethanol incubation of C2C12 myotubes exacerbated myotube atrophy and dysregulation of anabolic and catabolic signalling pathways associated with either component individually. Ubiquitin proteasome‐mediated protein breakdown appears to play an important role in myotube protein loss with ethanol and ammonia.

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Chronic Alcohol and Skeletal Muscle

Bourgeois

Levitt

Molina

et al. 2022

Handbook of Substance Misuse and Addictions

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Alcohol Intoxication Impairs Phosphorylation of S6K1 and S6 in Skeletal Muscle Independently of Ethanol Metabolism

Cited by 51 publications

References 20 publications

Skeletal muscle protein synthesis and degradation exhibit sexual dimorphism after chronic alcohol consumption but not acute intoxication

Skeletal muscle protein synthesis and degradation exhibit sexual dimorphism after chronic alcohol consumption but not acute intoxication

The metabolic and molecular mechanisms of hyperammonaemia‐ and hyperethanolaemia‐induced protein catabolism in skeletal muscle cells

Chronic Alcohol and Skeletal Muscle

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