Rate of protein synthesis in skeletal muscle of normal man and patients with muscular dystrophy: A reassessment

1988 ◽  
Vol 74 (3) ◽  
pp. 237-240 ◽  
Author(s):  
D. Halliday ◽  
P. J. Pacy ◽  
K. N. Cheng ◽  
F. Dworzak ◽  
J. N. A. Gibson ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Protein ◽  
Normal Subjects ◽  
Quadriceps Muscle ◽  
Fed State ◽  
Synthetic Rate ◽  
New Finding ◽  
Normal Man ◽  
Relative Differences ◽  
Muscle Biopsies

1. Quadriceps muscle protein synthetic rate has been determined in healthy subjects in the post-absorptive (n = 18) and fed (n = 10) states and in patients with a variety of myopathies, by analysis of the enrichment of serial muscle biopsies taken during primed continuous infusion of l[1-13C]leucine. 2. Quadriceps protein synthetic rates in normal subjects were (mean ± sd) 0.046 ± 0.012 and 0.075 ± 0.014%/h in the post-absorptive and fed states respectively. These results are significantly lower than we previously reported (M. J. Rennie et al., Clinical Science, 1982, 63, 519–523 [1]) but show the same relative differences of direction and magnitude, confirming the effects of feeding previously reported. In patients with muscular dystrophy, muscle protein synthetic rate was, as previously reported [1], much lower in the fed state than in normal subjects. A new finding is that for patients with myotonic dystrophy the rate is also depressed in the postabortive state. 3. We suggest that the present estimates in post-absorptive and fed normal subjects be used as reference values for quadriceps mixed muscle protein synthetic rate.

Creatine supplementation has no effect on human muscle protein turnover at rest in the postabsorptive or fed states

2003 ◽  
Vol 284 (4) ◽  
pp. E764-E770 ◽  
Author(s):  
Magali Louis ◽  
Jacques R. Poortmans ◽  
Marc Francaux ◽  
Eric Hultman ◽  
Jacques Berré ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Muscle Protein ◽  
Creatine Supplementation ◽  
Quadriceps Muscle ◽  
Protein Breakdown ◽  
Fed State ◽  
Muscle Protein Breakdown ◽  
Before And After ◽  
Total Creatine ◽  
Myofibrillar Protein Synthesis

Dietary creatine supplementation is associated with increases in muscle mass, but the mechanism is unknown. We tested the hypothesis that creatine supplementation enhanced myofibrillar protein synthesis (MPS) and diminished muscle protein breakdown (MPB) in the fed state. Six healthy men (26 ± 7 yr, body mass index 22 ± 4 kg/m2) were studied twice, 2–4 wk apart, before and after ingestion of creatine (21 g/day, 5 days). We carried out two sets of measurements within 5.5 h of both MPS (by incorporation of [1-13C]leucine in quadriceps muscle) and MPB (as dilution of [1-13C]leucine or [2H5]phenylalanine across the forearm); for the first 3 h, the subjects were postabsorptive but thereafter were fed orally (0.3 g maltodextrin and 0.083 g protein · kg body wt−1 · h−1). Creatine supplementation increased muscle total creatine by ∼30% ( P < 0.01). Feeding had significant effects, doubling MPS ( P < 0.001) and depressing MPB by ∼40% ( P < 0.026), but creatine had no effect on turnover in the postabsorptive or fed states. Thus any increase in muscle mass accompanying creatine supplementation must be associated with increased physical activity.

Decrease in human quadriceps muscle protein turnover consequent upon leg immobilization

1987 ◽  
Vol 72 (4) ◽  
pp. 503-509 ◽  
Author(s):  
J. N. A. Gibson ◽  
D. Halliday ◽  
W. L. Morrison ◽  
P. J. Stoward ◽  
G. A. Hornsby ◽  
...  
Keyword(s):  
Protein Turnover ◽  
Muscle Protein ◽  
Fibre Diameter ◽  
Quadriceps Muscle ◽  
Fibre Volume ◽  
Type I ◽  
Protein Breakdown ◽  
Muscle Protein Turnover ◽  
Muscle Protein Breakdown ◽  
Synthetic Rate

1. Quadriceps muscle protein turnover was assessed in the post-absorptive state in six men immediately after the end of unilateral leg immobilization (37 ± 4 days) in a plaster cast after tibial fracture. A primed-constant intravenous infusion of l-[1-13C]leucine was administered over 7 h. Quadriceps needle biopsies, taken bilaterally at the end of the infusion, were analysed for muscle protein leucine enrichment with 13C. 2. Quadriceps muscle protein synthetic rate, calculated from the fractional incorporation of [13C]leucine into protein compared with the average enrichment of blood α-ketoisocaproate, was 0.046 ±0.012%/h in the uninjured leg, but was only 0.034 ±0.007%/h in the quadriceps of the previously fractured leg (P > 0.05, means ± sd). 3. Muscle RNA activity (i.e. protein synthetic rate per RNA) fell from 0.27 ±0.08 μg of protein synthesized h−1 μg−1 of RNA in the control leg to 0.14 ±0.03 μg of protein synthesized h−1 μg−1 of RNA in the immobilized leg (P > 0.02). 4. Immobilization was associated with a significant atrophy of type I muscle fibres (mean diameter 69.5 ±21 μm immobilized, 81.1 ±18 μm control, P > 0.05), but no significant change occurred in type II fibre diameter. Mean quadriceps fibre volume calculated from the values for fibre diameter and percentage of each fibre type, was smaller in the injured leg by 10.6%; this value was near to the calculated difference in muscle thigh volume (calculated from thigh circumference and skin-fold thickness) which was less by 8.3%. 5. From estimated mean daily values for quadriceps protein synthetic rate (1.65 ±0.44%/day in the control legs and 1.22±0.28%/day in the injured legs) and change in fibre volume, mean daily muscle protein breakdown rates were calculated as 1.65%/ day and 1.53%/day respectively, suggesting that muscle protein breakdown was not enhanced and may have fallen. 6. The results suggest a decrease in muscle protein turnover during limb immobilization in man, with the decrement in muscle mass being due mainly to a substantial (25%) depression of muscle protein synthesis.

Observations on Cardiac Output and ”Pulmonary Blood Volume” in Normal Man by External Recording of the Intracardiac Flow of 131I Labelled Albumin

1961 ◽  
Vol 1 (04) ◽  
pp. 353-379
Author(s):  
Jacques Lammerant ◽  
Norman Veall ◽  
Michel De Visscher
Keyword(s):  
Cardiac Output ◽  
Blood Volume ◽  
Normal Subjects ◽  
Published Data ◽  
Total Blood Volume ◽  
Total Blood ◽  
Pulmonary Blood Volume ◽  
Intracardiac Flow ◽  
Normal Man ◽  
Mean Circulation

Summary1. The technique for the measurement of cardiac output by external recording of the intracardiac flow of 131I labelled human serum albumin has been extended to provide a measure of the mean circulation time from right to left heart and hence a new approach to the estimation of the pulmonary blood volume.2. Values for the basal cardiac output in normal subjects and its variations with age are in good agreement with the previously published data of other workers.3. The pulmonary blood volume in normal man in the basal state was found to be 28.2 ± 0.6% of the total blood volume.4. There was no correlation between cardiac output and pulmonary blood volume in a series of normal subjects in the basal state.5. The increase in cardiac output during digestion was associated with a decrease in pulmonary blood volume equal to 6.3 ± 1.2% of the total blood volume, that is, about 280 ml.6. The increase in cardiac output during exercise was associated with a decrease in pulmonary blood volume equal to 4.5 ± 1.0% of the total blood volume, that is, about 200 ml.7. The increase in cardiac output attributed to alarm is not associated with a decrease in pulmonary blood volume, the latter may in fact be increased.8. The total blood volume is advocated as a standard of reference for studies of this type in normal subjects in preference to body weight or surface area.9. The significance of these results and the validity of the method are discussed.

scholarly journals Muscle Protein Alterations in LGMD2I Patients With Different Mutations in the Fukutin-related Protein Gene

2008 ◽  
Vol 56 (11) ◽  
pp. 995-1001 ◽  
Author(s):  
Lydia U. Yamamoto ◽  
Fernando J. Velloso ◽  
Bruno L. Lima ◽  
Luciana L.Q. Fogaça ◽  
Flávia de Paula ◽  
...  
Keyword(s):  
Muscle Protein ◽  
Congenital Muscular Dystrophy ◽  
Clinical Severity ◽  
Variable Degree ◽  
Related Protein ◽  
Collagen Vi ◽  
Rimmed Vacuoles ◽  
Calpain 3 ◽  
Protein Alterations ◽  
Muscle Biopsies

Fukutin-related protein (FKRP) is a protein involved in the glycosylation of cell surface molecules. Pathogenic mutations in the FKRP gene cause both the more severe congenital muscular dystrophy Type 1C and the milder Limb-Girdle Type 2I form (LGMD2I). Here we report muscle histological alterations and the analysis of 11 muscle proteins: dystrophin, four sarcoglycans, calpain 3, dysferlin, telethonin, collagen VI, α-DG, and α2-laminin, in muscle biopsies from 13 unrelated LGMD2I patients with 10 different FKRP mutations. In all, a typical dystrophic pattern was observed. In eight patients, a high frequency of rimmed vacuoles was also found. A variable degree of α2-laminin deficiency was detected in 12 patients through immunofluorescence analysis, and 10 patients presented α-DG deficiency on sarcolemmal membranes. Additionally, through Western blot analysis, deficiency of calpain 3 and dystrophin bands was found in four and two patients, respectively. All the remaining proteins showed a similar pattern to normal controls. These results suggest that, in our population of LGMD2I patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of α2-laminin and α-DG on sections are prevalent, independently of mutation type or clinical severity.

Adaptation to prolonged starvation in the rat: curtailment of skeletal muscle proteolysis

1981 ◽  
Vol 241 (4) ◽  
pp. E321-E327 ◽  
Author(s):  
M. N. Goodman ◽  
M. A. McElaney ◽  
N. B. Ruderman
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Early Event ◽  
Body Protein ◽  
Fed State ◽  
Prolonged Starvation ◽  
Obese Rats ◽  
Old Rats

Previous studies have established that 16-wk-old nonobese and obese rats conserve body protein during prolonged starvation. To determine the basis for this, protein synthesis and degradation in skeletal muscle were evaluated in the isolated perfused hindquarters of these rats, in the fed state and when starved for 2, 5, 10, and 11 days. Rats aged 4 and 8 wk were used as a comparison. The results indicate that the response to starvation depends on several factors: the age of the rat, its degree of adiposity, and the duration of the fast. An early event in starvation was a decline in muscle protein synthesis. This occurred in all groups, albeit this reduction occurred more slowly in the older rats. A later response to starvation was an increase in muscle proteolysis. This occurred between 2 and 5 days in the 8-wk-old rats. In 16-wk-old rats it did not occur until between 5 and 10 days, and it was preceded by a period of decreased proteolysis. In 16-wk-old obese rats, a decrease in proteolysis persisted for upwards of 10 days and the secondary increase was not noted during the period of study. The data suggest that the ability of older and more obese rats to conserve body protein during starvation is due, in part, to a curtailment of muscle proteolysis. This adaptation seems to correlate with the availability of lipid fuels.

Enhanced response of muscle protein synthesis and plasma insulin to food intake in suckled rats

1993 ◽  
Vol 265 (2) ◽  
pp. R334-R340 ◽  
Author(s):  
T. A. Davis ◽  
M. L. Fiorotto ◽  
H. V. Nguyen ◽  
P. J. Reeds
Keyword(s):  
Protein Synthesis ◽  
Food Intake ◽  
Plasma Insulin ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fed State ◽  
Fasting And Refeeding ◽  
Old Rats ◽  
Amino Acid Concentrations

To compare the sensitivity of muscle protein synthesis to food intake in neonatal and weaned rats, 5- and 16-day-old suckled rats and 28-day-old weaned rats were either fed, fasted for 8-10 h, or refed for 1-4 h after an 8-h fast. Protein synthesis was measured in vivo in soleus and plantaris muscles with a large dose of L-[4-3H]phenylalanine. In fed rats, fractional rates of protein synthesis (KS) decreased with age. Fasting decreased KS, and refeeding increased KS most in 5-day-old animals, less in 16-day-old rats, and least in 28-day-old rats. In 5-day-old rats, there were no differences in KS between soleus and plantaris muscles in the fed state and after fasting and refeeding; at 28 days, KS was higher in soleus than in plantaris in fed rats, and the soleus did not respond to fasting and refeeding. In rats at all three ages, the concentration of most plasma amino acids decreased during fasting; when 5-day-old rats were refed, plasma amino acid concentrations increased, but not to the levels in the fed state. Plasma insulin concentrations increased with age. Plasma insulin concentrations decreased more rapidly with fasting and increased more extensively with refeeding in 5-day-old rats than in older rats. These results suggest that muscle protein synthesis is more responsive to food intake in young suckled rats than in older suckled or weaned rats; this increased responsiveness is accompanied by greater changes in circulating insulin concentrations.

Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis

2001 ◽  
Vol 91 (3) ◽  
pp. 1041-1047 ◽  
Author(s):  
G. Parise ◽  
S. Mihic ◽  
D. MacLennan ◽  
K. E. Yarasheski ◽  
M. A. Tarnopolsky
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Fat Free Mass ◽  
Whole Body ◽  
Synthetic Rate ◽  
Fractional Synthetic Rate ◽  
Before And After ◽  
Total Creatine ◽  
Plasma Leucine

Creatine monohydrate (CrM) supplementation during resistance exercise training results in a greater increase in strength and fat-free mass than placebo. Whether this is solely due to an increase in intracellular water or whether there may be alterations in protein turnover is not clear at this point. We examined the effects of CrM supplementation on indexes of protein metabolism in young healthy men ( n = 13) and women ( n = 14). Subjects were randomly allocated to CrM (20 g/day for 5 days followed by 5 g/day for 3–4 days) or placebo (glucose polymers) and tested before and after the supplementation period under rigorous dietary and exercise controls. Muscle phosphocreatine, creatine, and total creatine were measured before and after supplementation. A primed-continuous intravenous infusion of l-[1-13C]leucine and mass spectrometry were used to measure mixed-muscle protein fractional synthetic rate and indexes of whole body leucine metabolism (nonoxidative leucine disposal), leucine oxidation, and plasma leucine rate of appearance. CrM supplementation increased muscle total creatine (+13.1%, P < 0.05) with a trend toward an increase in phosphocreatine (+8.8%, P = 0.09). CrM supplementation did not increase muscle fractional synthetic rate but reduced leucine oxidation (−19.6%) and plasma leucine rate of appearance (−7.5%, P < 0.05) in men, but not in women. CrM did not increase total body mass or fat-free mass. We conclude that short-term CrM supplementation may have anticatabolic actions in some proteins (in men), but CrM does not increase whole body or mixed-muscle protein synthesis.

Bradykinin and renal function in normal man: effects of adrenergic blockade

1965 ◽  
Vol 209 (4) ◽  
pp. 844-848 ◽  
Author(s):  
John R. Gill ◽  
Kenneth L. Melmon ◽  
Louis Gillespie ◽  
Frederic C. Bartter
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Normal Subjects ◽  
Adrenergic Blockade ◽  
Disease States ◽  
Lower Blood ◽  
Normal Man ◽  
Endogenous Release ◽  
Infusion Of Norepinephrine ◽  
As Effects

Renal function was studied in five normal subjects during the infusion of bradykinin at 0.1 and 0.4 µg/kg per min, and in four additional normal subjects during the infusion of norepinephrine at dosages beginning with 1–3 µg/ min. Bradykinin at both dosages decreased glomerular filtration rate (GFR) and tended to increase renal blood flow (ERPF). It increased sodium excretion (UNaV) at the lower dosage, but did not increase it further at the higher dosage. At all dosages, norepinephrine decreased ERPF and UNaV. The effects of bradykinin cannot be explained solely as effects of norepinephrine released by the bradykinin. During adrenergic blockade produced by guanethidine, bradykinin, 0.1 µg/kg per min, slightly decreased GFR and UNaV; at 0.4 µg/kg per min, it further decreased GFR and UNaV and tended to decrease ERPF as well. It did not lower blood pressure. The data suggest that in normal man, bradykinin increases UNaV only at low dosages. During adrenergic blockade, endogenous release of angiotensin could have prevented bradykinin from lowering blood pressure and could have caused the decreases in GFR, ERPF, and UNaV. A possible role is suggested for bradykinin in the physiologic control of renal function, and as a causative agent in producing the changes in renal function found in certain disease states characterized by excessive production of kinins.

scholarly journals Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy

Neurology ◽  
2020 ◽  
Vol 94 (21) ◽  
pp. e2270-e2282 ◽  
Author(s):  
Diane E. Frank ◽  
Frederick J. Schnell ◽  
Cody Akana ◽  
Saleh H. El-Husayni ◽  
Cody A. Desjardins ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Exon Skipping ◽  
Study Drug ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Dystrophin Protein ◽  
Muscle Biopsies

ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrials.gov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

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