scholarly journals Mechanisms Underlying Muscle Protein Imbalance Induced by Alcohol

2018 ◽  
Vol 38 (1) ◽  
pp. 197-217 ◽  
Author(s):  
Scot R. Kimball ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Cardiac Contractility ◽  
Metabolic Phenotype ◽  
Alcoholic Myopathy ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Induced Changes ◽  
Skeletal Muscle Strength

Both acute intoxication and longer-term cumulative ingestion of alcohol negatively impact the metabolic phenotype of both skeletal and cardiac muscle, independent of overt protein calorie malnutrition, resulting in loss of skeletal muscle strength and cardiac contractility. In large part, these alcohol-induced changes are mediated by a decrease in protein synthesis that in turn is governed by impaired activity of a protein kinase, the mechanistic target of rapamycin (mTOR). Herein, we summarize recent advances in understanding mTOR signal transduction, similarities and differences between the effects of alcohol on this central metabolic controller in skeletal muscle and in the heart, and the effects of acute versus chronic alcohol intake. While alcohol-induced alterations in global proteolysis via activation of the ubiquitin-proteasome pathway are equivocal, emerging data suggest alcohol increases autophagy in muscle. Further studies are necessary to define the relative contributions of these bidirectional changes in protein synthesis and autophagy in the etiology of alcoholic myopathy in skeletal muscle and the heart.

Mechanisms of Cancer Cachexia

2009 ◽  
Vol 89 (2) ◽  
pp. 381-410 ◽  
Author(s):  
Michael J. Tisdale
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Adipose Tissue ◽  
Protein Degradation ◽  
Initiation Factor ◽  
Tissue Loss ◽  
Α Subunit ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the α-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFκB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-α, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.

scholarly journals Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle

2015 ◽  
Vol 309 (12) ◽  
pp. E981-E994 ◽  
Author(s):  
Jennifer L. Steiner ◽  
Kristen T. Crowell ◽  
Scot R. Kimball ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Cecal Ligation ◽  
Skeletal Muscle Atrophy ◽  
Matched Pair ◽  
Mtorc1 Signaling ◽  
Ubiquitin Proteasome ◽  
Lysosomal System

Sepsis-induced skeletal muscle atrophy and weakness are due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD1 (regulated in development and DNA damage-1) protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis-induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1−/− or wild-type (WT) mice, and end points were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice, whereas REDD1 was absent in REDD1−/− muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 Thr389, rpS6 Ser240/244, 4E-BP1 Ser65) in WT but not REDD1−/− mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1−/− mice despite unaltered PDK1, PP2A, or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 Ser757 phosphorylation and p62 abundance and increased LC3B-II/I in WT mice, whereas these changes were absent in septic REDD1−/− mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNFα, MuRF1, and atrogin1 mRNA expression. Lastly, 5-day survival in a separate set of septic mice did not differ between WT and REDD1−/− mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis.

scholarly journals The Molecular Mechanisms of Calpains Action on Skeletal Muscle Atrophy

2016 ◽  
pp. 547-560 ◽  
Author(s):  
J. HUANG ◽  
X. ZHU
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Protein ◽  
Therapeutic Interventions ◽  
Skeletal Muscle Atrophy ◽  
Akt Phosphorylation ◽  
Downstream Effects ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Skeletal muscle atrophy is associated with a loss of muscle protein which may result from both increased proteolysis and decreased protein synthesis. Investigations on cell signaling pathways that regulate muscle atrophy have promoted our understanding of this complicated process. Emerging evidence implicates that calpains play key roles in dysregulation of proteolysis seen in muscle atrophy. Moreover, studies have also shown that abnormally activated calpain results muscle atrophy via its downstream effects on ubiquitin-proteasome pathway (UPP) and Akt phosphorylation. This review will discuss the role of calpains in regulation of skeletal muscle atrophy mainly focusing on its collaboration with either UPP or Akt in atrophy conditions in hope to stimulate the interest in development of novel therapeutic interventions for skeletal muscle atrophy.

IGF-I has no effect on postexercise suppression of the ubiquitin-proteasome system in rat skeletal muscle

2002 ◽  
Vol 92 (6) ◽  
pp. 2277-2284 ◽  
Author(s):  
Anthony J. Kee ◽  
Alan J. Taylor ◽  
Anthony R. Carlsson ◽  
Andre Sevette ◽  
Ross C. Smith ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Exercise ◽  
Protein Turnover ◽  
Muscle Protein ◽  
Male Rats ◽  
Ubiquitin Proteasome Pathway ◽  
Muscle Protein Turnover ◽  
Igf I ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Both exercise and insulin-like growth factor I (IGF-I) are known to have major hypertrophic effects in skeletal muscle; however, the interactive effect of exogenous IGF-I and exercise on muscle protein turnover or the ubiquitin-proteasome pathway has not been reported. In the present study, we have examined the interaction between endurance exercise training and IGF-I treatment on muscle protein turnover and the ubiquitin-proteasome pathway in the postexercise period. Adult male rats (270–280 g) were randomized to receive 5 consecutive days of progressive treadmill exercise and/or IGF-I treatment (1 mg · kg body wt−1 · day−1). Twenty-four hours after the last bout of exercise, the rate of protein breakdown in incubated muscles was significantly reduced compared with that in unexercised rats. This was associated with a significant reduction in the chymotrypsin-like activity of the proteasome and the rate of ubiquitin-proteasome-dependent casein hydrolysis in muscle extracts from exercised compared with unexercised rats. In contrast, the muscle expression of the 20S proteasome subunit β-1, ubiquitin, and the 14-kDa E2 ubiquitin-conjugating enzyme was not altered by exercise or IGF-I treatment 24 h postexercise. Exercise had no effect on the rates of total mixed muscle protein synthesis in incubated muscles 24 h postexercise. IGF-I treatment had no effect on muscle weights or the rates of protein turnover 24 h after endurance exercise. These results suggest that a suppression of the ubiquitin-proteasome proteolytic pathway after endurance exercise may contribute to the acute postexercise net protein gain.

Skeletal and cardiac muscle protein turnover during cold acclimation in young rats

2000 ◽  
Vol 278 (3) ◽  
pp. R705-R711 ◽  
Author(s):  
T. A. McAllister ◽  
J. R. Thompson ◽  
S. E. Samuels
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Cardiac Muscle ◽  
Cold Acclimation ◽  
Protein Turnover ◽  
Muscle Protein ◽  
Muscle Protein Turnover ◽  
Protein Mass ◽  
The Absolute

The effect of long-term cold exposure on skeletal and cardiac muscle protein turnover was investigated in young growing animals. Two groups of 36 male 28-day-old rats were maintained at either 5°C (cold) or 25°C (control). Rates of protein synthesis and degradation were measured in vivo on days 5, 10, 15, and 20. Protein mass by day 20 was ∼28% lower in skeletal muscle (gastrocnemius and soleus) and ∼24% higher in heart in cold compared with control rats ( P < 0.05). In skeletal muscle, the fractional rates of protein synthesis ( k syn) and degradation ( k deg) were not significantly different between cold and control rats, although k syn was lower (approximately −26%) in cold rats on day 5; consequent to the lower protein mass, the absolute rates of protein synthesis (approximately −21%; P < 0.05) and degradation (approximately −13%; P < 0.1) were lower in cold compared with control rats. In heart, overall, k syn(approximately +12%; P < 0.1) and k deg(approximately +22%; P < 0.05) were higher in cold compared with control rats; consequently, the absolute rates of synthesis (approximately +44%) and degradation (approximately +54%) were higher in cold compared with control rats ( P < 0.05). Plasma triiodothyronine concentration was higher ( P < 0.05) in cold compared with control rats. These data indicate that long-term cold acclimation in skeletal muscle is associated with the establishment of a new homeostasis in protein turnover with decreased protein mass and normal fractional rates of protein turnover. In heart, unlike skeletal muscle, rates of protein turnover did not appear to immediately return to normal as increased rates of protein turnover were observed beyond day 5. These data also indicate that increased rates of protein turnover in skeletal muscle are unlikely to contribute to increased metabolic heat production during cold acclimation.

Mergla K + channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway

2006 ◽  
Vol 20 (9) ◽  
pp. 1531-1533 ◽  
Author(s):  
Xun Wang ◽  
Gregory H. Hockerman ◽  
Henry W. Green ◽  
Charles F. Babbs ◽  
Sulma I. Mohammad ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
K Channel ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway
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