scholarly journals Stimulation of skeletal muscle myofibrillar protein synthesis, p70 S6 kinase phosphorylation, and ribosomal protein S6 phosphorylation by inhibition of myostatin in mature mice

2009 ◽  
Vol 296 (3) ◽  
pp. E567-E572 ◽  
Author(s):  
Stephen Welle ◽  
Kerri Burgess ◽  
Sangeeta Mehta
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Myofibrillar Protein ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
S6 Kinase ◽  
P70 S6 Kinase ◽  
Ribosomal Protein S6 ◽  
The Mean ◽  
Myofibrillar Protein Synthesis

Knocking out myostatin activity during development increases the rate of muscle protein synthesis. The present study was done to determine whether postdevelopmental loss of myostatin activity stimulates myofibrillar protein synthesis and the phosphorylation of some of the proteins involved in regulation of protein synthesis rate. Myostatin activity was inhibited for 4 days, in 4- to 5-mo-old male mice, with injections of an anti-myostatin antibody (JA16). The mean myofibrillar synthesis rate increased 19% ( P < 0.01) relative to the mean rate in saline-treated mice, as determined by incorporation of deuterium-labeled phenylalanine. JA16 increased phosphorylation of p70 S6 kinase (S6K) and ribosomal protein S6 (rpS6) 1.9-fold ( P < 0.05). It did not affect phosphorylation of eukaryotic initiation factor 4E-binding protein-1 or Akt. Microarrays and real-time PCR analyses indicated that JA16 administration did not selectively enrich levels of mRNAs encoding myofibrillar proteins, ribosomal proteins, or translation initiation and elongation factors. Rapamycin treatment did not affect the rate of myofibrillar protein synthesis whether or not the mice received JA16 injections, although it eliminated the phosphorylation of S6K and rpS6. We conclude that the normal level of myostatin activity in mature muscle is sufficient to inhibit myofibrillar synthesis rate and phosphorylation of S6K and rpS6. Reversal of the inhibition of myofibrillar synthesis with an anti-myostatin antibody is not dependent on mTOR activation.

scholarly journals Essential Amino Acid-Enriched Diet Alleviates Dexamethasone-Induced Loss of Muscle Mass and Function through Stimulation of Myofibrillar Protein Synthesis and Improves Glucose Metabolism in Mice

Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 84
Author(s):  
Yeongmin Kim ◽  
Sanghee Park ◽  
Jinseok Lee ◽  
Jiwoong Jang ◽  
Jiyeon Jung ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Glucose Metabolism ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Myofibrillar Protein ◽  
Treadmill Running ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Myofibrillar Protein Synthesis ◽  
Stimulation Of

Dexamethasone (DEX) induces dysregulation of protein turnover, leading to muscle atrophy and impairment of glucose metabolism. Positive protein balance, i.e., rate of protein synthesis exceeding rate of protein degradation, can be induced by dietary essential amino acids (EAAs). In this study, we investigated the roles of an EAA-enriched diet in the regulation of muscle proteostasis and its impact on glucose metabolism in the DEX-induced muscle atrophy model. Mice were fed normal chow or EAA-enriched chow and were given daily injections of DEX over 10 days. We determined muscle mass and functions using treadmill running and ladder climbing exercises, protein kinetics using the D2O labeling method, molecular signaling using immunoblot analysis, and glucose metabolism using a U-13C6 glucose tracer during oral glucose tolerance test (OGTT). The EAA-enriched diet increased muscle mass, strength, and myofibrillar protein synthesis rate, concurrent with improved glucose metabolism (i.e., reduced plasma insulin concentrations and increased insulin sensitivity) during the OGTT. The U-13C6 glucose tracing revealed that the EAA-enriched diet increased glucose uptake and subsequent glycolytic flux. In sum, our results demonstrate a vital role for the EAA-enriched diet in alleviating the DEX-induced muscle atrophy through stimulation of myofibrillar proteins synthesis, which was associated with improved glucose metabolism.

scholarly journals Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

2002 ◽  
Vol 277 (34) ◽  
pp. 30958-30967 ◽  
Author(s):  
Elena A. Goncharova ◽  
Dmitry A. Goncharov ◽  
Andrew Eszterhas ◽  
Deborah S. Hunter ◽  
Marilyn K. Glassberg ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
S6 Kinase ◽  
Kinase Activation ◽  
P70 S6 Kinase ◽  
Ribosomal Protein S6

Regulation of myofibrillar protein turnover during maturation in normal and undernourished rat pups

2000 ◽  
Vol 278 (4) ◽  
pp. R845-R854 ◽  
Author(s):  
Marta L. Fiorotto ◽  
Teresa A. Davis ◽  
Peter J. Reeds
Keyword(s):  
Protein Synthesis ◽  
Protein Turnover ◽  
Myofibrillar Protein ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Myofibrillar Proteins ◽  
Sarcoplasmic Proteins ◽  
Rat Pups ◽  
Sarcoplasmic Protein ◽  
Degradation Rates

The study tested the hypothesis that a higher rate of myofibrillar than sarcoplasmic protein synthesis is responsible for the rapid postdifferentiation accumulation of myofibrils and that an inadequate nutrient intake will compromise primarily myofibrillar protein synthesis. Myofibrillar (total and individual) and sarcoplasmic protein synthesis, accretion, and degradation rates were measured in vivo in well-nourished (C) rat pups at 6, 15, and 28 days of age and compared at 6 and 15 days of age with pups undernourished (UN) from birth. In 6-day-old C pups, a higher myofibrillar than sarcoplasmic protein synthesis rate accounted for the greater deposition of myofibrillar than sarcoplasmic proteins. The fractional synthesis rates of both protein compartments decreased with age, but to a greater degree for myofibrillar proteins (−54 vs. −42%). These decreases in synthesis rates were partially offset by reductions in degradation rates, and from 15 days, myofibrillar and sarcoplasmic proteins were deposited in constant proportion to one another. Undernutrition reduced both myofibrillar and sarcoplasmic protein synthesis rates, and the effect was greater at 6 (−25%) than 15 days (−15%). Decreases in their respective degradation rates minimized the effect of undernutrition on sarcoplasmic protein accretion from 4 to 8 days and on myofibrillar proteins from 13 to 17 days. Although these adaptations in protein turnover reduced overall growth of muscle mass, they mitigated the effects of undernutrition on the normal maturational changes in myofibrillar protein concentration.

scholarly journals Protein synthesis, myosin ATPase activity and myofibrillar protein composition in hearts from tumour-bearing rats and mice

1989 ◽  
Vol 264 (1) ◽  
pp. 191-198 ◽  
Author(s):  
C Drott ◽  
C Lönnroth ◽  
K Lundholm
Keyword(s):  
Protein Synthesis ◽  
Atpase Activity ◽  
Protein Composition ◽  
Myofibrillar Protein ◽  
Myosin Atpase ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Tumour Bearing ◽  
Myosin Atpase Activity ◽  
Rats And Mice

Growing rats and adult weight-stable mice bearing a transplantable methylcholanthrene-induced sarcoma were compared with animals with various states of malnutrition. Heart protein synthesis was measured in vivo. Myocardial RNA, myofibrillar protein composition and the Ca2+-activated ATPase activity in heavy chains of native myosin were measured. ‘Fingerprints’ were made from myosin by trypsin treatment to evaluate possible structural changes in the protein. Cardiac protein-synthesis rate was decreased by 20% in growing tumour-bearing rats, by 35% in protein-malnourished (rats) and by 47% in starved rats, compared with freely fed controls (P less than 0.05). Adult tumour-bearing mice showed no significant decrease in myocardial protein synthesis. Pair-weighed control mice had significantly depressed heart protein synthesis. Protein translational efficiency was maintained in both tumour-bearing rats and mice, but was decreased in several groups of malnourished control animals. The Ca2+-activated myosin ATPase activity was decreased in all groups of malnourished animals, including tumour-bearing mice and rats, without any evidence of a change in cardiac isomyosin composition. We conclude that loss of cardiac muscle mass in tumour disease is communicated by both depressed synthesis and increased degradation largely owing to anorexia and host malnutrition. Increased adrenergic sensitivity in hearts from tumour-bearing and malnourished animals is not communicated by increased Ca2+-activated ATPase activity. This may be down-regulated in all groups with malnutrition, without any observable alterations in the isomyosin profile.

Myofibrillar protein synthesis in young and old human subjects after three months of resistance training

1995 ◽  
Vol 268 (3) ◽  
pp. E422-E427 ◽  
Author(s):  
S. Welle ◽  
C. Thornton ◽  
M. Statt
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Myofibrillar Protein ◽  
Whole Body ◽  
Synthesis Rate ◽  
Vastus Lateralis Muscle ◽  
Body Protein ◽  
Men And Women ◽  
Older Subjects ◽  
Myofibrillar Protein Synthesis

Muscle protein synthesis is slower in healthy older men and women than in young adults, but whether this results from relative disuse rather than aging is unclear. The present study was done to examine rates of myofibrillar protein synthesis before and after a 3-mo progressive resistance exercise program in young and old men and women. Protein synthesis was determined by incorporation of the tracer L-[1-13C]leucine into myofibrillar proteins obtained from the vastus lateralis muscle by needle biopsy. Before exercise, mean fractional myofibrillar synthesis was 33% slower (P < 0.01) in nine older subjects (62-72 yr old, 5 men and 4 women) than in 9 young subjects (22-31 yr old, 5 men and 4 women). Initial strength, as determined by three-repetition-maximum tests, was significantly less in the older group. Strength and training weights increased similarly in young and old groups, when expressed in relation to baseline values. Posttraining myofibrillar synthesis was determined on the day after the final training session. There was not a significant change in fractional myofibrillar synthesis in either the young or the old group after training, and the rate in the older group remained 27% slower (P < 0.05). Whole body protein turnover increased approximately 10% only in the younger group, and 24-h urinary 3-methylhistidine excretion (an index of myofibrillar proteolysis) was not significantly affected by training. These data suggest that the slower myofibrillar synthesis rate in older subjects cannot be explained by disuse.

scholarly journals Phosphatase control of 4E-BP1 phosphorylation state is central for glycolytic regulation of retinal protein synthesis

2015 ◽  
Vol 309 (6) ◽  
pp. E546-E556 ◽  
Author(s):  
Thomas W. Gardner ◽  
Steven F. Abcouwer ◽  
Mandy K. Losiewicz ◽  
Patrice E. Fort
Keyword(s):  
Protein Synthesis ◽  
Ex Vivo ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Retinal Protein ◽  
Eif2α Phosphorylation ◽  
Ribosomal Protein S6 ◽  
Metabolic Activities

Control of protein synthesis in insulin-responsive tissues has been well characterized, but relatively little is known about how this process is regulated in nervous tissues. The retina exhibits a relatively high protein synthesis rate, coinciding with high basal Akt and metabolic activities, with the majority of retinal ATP being derived from aerobic glycolysis. We examined the dependency of retinal protein synthesis on the Akt-mTOR signaling and glycolysis using ex vivo rat retinas. Akt inhibitors significantly reduced retinal protein synthesis but did not affect glycolytic lactate production. Surprisingly, the glycolytic inhibitor 2-deoxyglucose (2-DG) markedly inhibited Akt1 and Akt3 activities, as well as protein synthesis. The effects of 2-DG, and 2-fluorodeoxyglucose (2-FDG) on retinal protein synthesis correlated with inhibition of lactate production and diminished ATP content, with all these effects reversed by provision of d-mannose. 2-DG treatment was not associated with increased AMPK, eEF2, or eIF2α phosphorylation; instead, it caused rapid dephosphorylation of 4E-BP1. 2-DG reduced total mTOR activity by 25%, but surprisingly, it did not reduce mTORC1 activity, as indicated by unaltered raptor-associated mTOR autophosphorylation and ribosomal protein S6 phosphorylation. Dephosphorylation of 4E-BP1 was largely prevented by inhibition of PP1/PP2A phosphatases with okadaic acid and calyculin A, and inhibition of PPM1 phosphatases with cadmium. Thus, inhibition of retinal glycolysis diminished Akt and protein synthesis coinciding with accelerated dephosphorylation of 4E-BP1 independently of mTORC1. These results demonstrate a novel mechanism regulating protein synthesis in the retina involving an mTORC1-independent and phosphatase-dependent regulation of 4E-BP1.

Myofibrillar protein synthesis in young and old men

1993 ◽  
Vol 264 (5) ◽  
pp. E693-E698 ◽  
Author(s):  
S. Welle ◽  
C. Thornton ◽  
R. Jozefowicz ◽  
M. Statt
Keyword(s):  
Protein Synthesis ◽  
Lean Body Mass ◽  
Body Mass ◽  
Myofibrillar Protein ◽  
Whole Body ◽  
Synthesis Rate ◽  
Body Protein ◽  
Creatinine Excretion ◽  
Significant Difference ◽  
Myofibrillar Protein Synthesis

We tested the hypothesis that healthy older men (> 60 yr old) have a slower rate of myofibrillar protein synthesis than young men (< 35 yr old). Myofibrillar protein synthesis was determined by the in vivo incorporation of L-[1-13C]leucine into myofibrillar proteins obtained by muscle biopsy. Subjects were eight young (21-31 yr) and eight older (62-81 yr) men, all healthy and moderately active. There was no significant difference in the mean height and weight of the two age groups, but the older group had 12% less lean body mass (determined by 40K counting) and 21% less muscle mass (estimated by urinary creatinine excretion). Upper leg strength was approximately one-third lower in the older subjects according to isokinetic dynamometry. The fractional rate of myofibrillar protein synthesis was 28% slower in the older group (0.039 +/- 0.009 vs. 0.054 +/- 0.010 %/h, mean +/- SD, P < 0.01). Total myofibrillar protein synthesis, estimated as total myofibrillar mass (from creatinine excretion) times the fractional synthesis rate, was 44% slower in the older group (1.4 vs. 2.5 g/h, P < 0.001). Whole body protein synthesis, assessed as the difference between leucine disappearance rate and leucine oxidation, was marginally slower (8%, P = 0.10) in the older group, but not when the data were adjusted for lean body mass. Myofibrillar protein synthesis was a smaller fraction of whole body protein synthesis in the older group (12 vs. 19%). Reduced myofibrillar protein synthesis may be an important mechanism of the muscle atrophy associated with aging.

scholarly journals Amino acid availability and age affect the leucine stimulation of protein synthesis and eIF4F formation in muscle

2007 ◽  
Vol 293 (6) ◽  
pp. E1615-E1621 ◽  
Author(s):  
Jeffery Escobar ◽  
Jason W. Frank ◽  
Agus Suryawan ◽  
Hanh V. Nguyen ◽  
Teresa A. Davis
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

We have previously shown that a physiological increase in plasma leucine for 60 and 120 min increases translation initiation factor activation in muscle of neonatal pigs. Although muscle protein synthesis is increased by leucine at 60 min, it is not maintained at 120 min, perhaps because of the decrease in plasma amino acids (AA). In the present study, 7- and 26-day-old pigs were fasted overnight and infused with leucine (0 or 400 μmol·kg−1·h−1) for 120 min to raise leucine within the postprandial range. The leucine was infused in the presence or absence of a replacement AA mixture (without leucine) to maintain baseline plasma AA levels. AA administration prevented the leucine-induced reduction in plasma AA in both age groups. At 7 days, leucine infusion alone increased eukaryotic initiation factor (eIF) 4E binding protein-1 (4E-BP1) phosphorylation, decreased inactive 4E-BP1·eIF4E complex abundance, and increased active eIF4G·eIF4E complex formation in skeletal muscle; leucine infusion with replacement AA also stimulated these, as well as 70-kDa ribosomal protein S6 kinase, ribosomal protein S6, and eIF4G phosphorylation. At 26 days, leucine infusion alone increased 4E-BP1 phosphorylation and decreased the inactive 4E-BP1·eIF4E complex only; leucine with AA also stimulated these, as well as 70-kDa ribosomal protein S6 kinase and ribosomal protein S6 phosphorylation. Muscle protein synthesis was increased in 7-day-old (+60%) and 26-day-old (+40%) pigs infused with leucine and replacement AA but not with leucine alone. Thus the ability of leucine to stimulate eIF4F formation and protein synthesis in skeletal muscle is dependent on AA availability and age.

p70 Ribosomal protein S6 kinase (Rps6kb1): an update

2014 ◽  
Vol 67 (12) ◽  
pp. 1019-1025 ◽  
Author(s):  
Farnaz Bahrami-B ◽  
Parvin Ataie-Kachoie ◽  
Mohammad H Pourgholami ◽  
David L Morris
Keyword(s):  
Protein Synthesis ◽  
Ribosomal Protein ◽  
Ribosomal Proteins ◽  
Ribosomal Subunit ◽  
Mtor Inhibitors ◽  
Therapeutic Index ◽  
Drug Induced ◽  
S6 Kinase ◽  
Ribosomal Protein S6 ◽  
Ribosomal Protein S6 Kinase

The Rps6kb1 gene encodes the 70 kDa ribosomal protein S6 kinase (p70S6K), which is a serine/threonine kinase regulated by phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. p70S6K plays a crucial role in controlling cell cycle, growth and survival. The PI3K/mTOR signalling pathway is one of the major mechanisms for controlling cell survival, proliferation and metabolism and is the central regulator of translation of some components of protein synthesis system. Upon activation, this kinase phosphorylates S6 protein of ribosomal subunit 40S resulting in selective translation of unique family of mRNAs that contain oligopyrimidine tract on 5’ transcriptional site (5′TOP). 5′TOP mRNAs are coding the components of translational apparatus including ribosomal proteins and elongation factors. Due to the role of p70S6K in protein synthesis and also its involvement in a variety of human diseases ranging from diabetes and obesity to cancer, p70S6K is now being considered as a new therapeutic target for drug development. Furthermore, p70S6K acts as a biomarker for response to immunosuppressant as well as anticancer effects of inhibitors of the mTOR. Because of the narrow therapeutic index of mTOR inhibitors, drug monitoring is essential, and this is usually done by measuring blood drug levels, therapeutic response and drug-induced adverse effects. Recent studies have suggested that plasma p70S6K is a reliable index for the monitoring of patient response to mTOR inhibitors. Therefore, a better understanding of p70S6K and its role in various pathological conditions could enable the development of strategies to aid diagnosis, prognosis and treatment schedules.

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