Flexor Injury Rehabilitation Splint Trial (FIRST): protocol for a pragmatic randomised controlled trial comparing three splints for finger flexor tendon repairs.

BACKGROUND: Without surgical repair, flexor tendon injuries do not heal and patients' ability to bend fingers and grip objects is impaired. However, flexor tendon repair surgery also requires optimal rehabilitation. There are currently three custom-made splints used in the rehabilitation of zone I/II flexor tendon repairs, each with different assumed harm/benefit profiles: the dorsal forearm and hand-based splint (long), the Manchester short splint (short), and the relative motion flexion splint (mini). There is, however, no robust evidence as to which splint, if any, is most clinical or cost effective. The Flexor Injury Rehabilitation Splint Trial (FIRST) was designed to address this evidence gap. METHODS: FIRST is a parallel group, superiority, analyst-blind, multi-centre, individual participant-randomised controlled trial. Participants will be assigned 1:1:1 to receive either the long, short, or mini splint. We aim to recruit 429 participants undergoing rehabilitation following zone I/II flexor tendon repair surgery. Potential participants will initially be identified prior to surgery, in NHS hand clinics across the UK, and consented and randomised at their splint fitting appointment post-surgery. The primary outcome will be the mean post-randomisation score on the patient-reported wrist and hand evaluation measure (PRWHE), assessed at 6, 12, 26, and 52 weeks post randomisation. Secondary outcome measures include blinded grip strength and active range of movement (AROM) assessments, adverse events, adherence to the splinting protocol (measured via temperature sensors inserted into the splints), quality of life assessment, and further patient-reported outcomes. An economic evaluation will assess the cost-effectiveness of each splint, and a qualitative sub-study will evaluate participants' preferences for, and experiences of wearing, the splints. Furthermore, a mediation analysis will determine the relationship between patient preferences, splint adherence, and splint effectiveness. DISCUSSION: FIRST will compare the three splints with respect to clinical efficacy, complications, quality of life and cost-effectiveness. FIRST is a pragmatic trial which will recruit from 26 NHS sites to allow findings to be generalisable to current clinical practice in the UK. It will also provide significant insights into patient experiences of splint wear and how adherence to splinting may impact outcomes. TRIAL REGISTRATION: ISRCTN: 10236011.

The effectiveness of cognitive behavioural therapy for patients with concurrent hand and psychological disorders.

We investigated the effectiveness of cognitive behavioural therapy (CBT) for patients with psychological disorders thought to be influencing recovery from elective and traumatic hand conditions. Demographic data and psychological assessment scores (Primary Health Questionnaire 9 (PHQ9), General Anxiety Disorder Assessment (GAD7), Impact of Event Scale (IES)) were prospectively collected before and after CBT treatment. One hundred and fourteen patients underwent CBT with 81 completing treatment. Full data was available for 78 (68%) patients. Mean age was 43 (range 13-84) and 63% were women. Sixty-one per cent had sustained a traumatic hand injury. PHQ9, GAD7 and IES scores decreased significantly following treatment. Many patients with hand conditions have associated psychological problems that may influence outcome. CBT in a hand unit setting appears to be an effective treatment. Further research with a control group should investigate whether CBT improves psychological health or if this may occur as patients recover from their physical hand disorder regardless of CBT.Level of evidence: IV.

A Review of Outcome Reporting Practices after Flexor Tendon Repair in Zones 1 and 2.

Background: Outcome reporting following flexor tendon repair has historically concentrated on range of movement. Recently, there has been an increase in the use of patient-reported outcome measures (PROMs). At present, there is no agreed set of outcomes to report following flexor tendon repair. The aim of this study is to review outcome reporting practices after flexor tendon repair in zones 1 and 2. Methods: A search of Ovid MEDLINE, Ovid EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between 1 January 1980 and 31 December 2019 was performed to identify the studies that reported outcomes following the repair of flexor tendons in zones 1 and 2. Study characteristics and data with regard to the reporting of eight outcome domains was extracted: functional outcome (quantitative), functional outcome (subjective), activities of daily living (ADL), satisfaction/quality of life, post-treatment recovery, resources, aesthetics and safety. Results: A total of 94 out of 4,118 articles identified were included in the review. All studies reported range of motion using 17 different methods of measurement. Eleven studies defined measurement methods incorrectly or unclearly. Only 16 studies reported PROMs, with only one reporting data on assessment of quality of life. Eighteen studies reported time away from employment. Minimal data on resource utilisation and aesthetics were included. Conclusion: This review highlights wide heterogeneity and paucity of data reporting clinical outcomes of flexor tendon surgery. The development of a core outcome set that would ensure essential outcomes are correctly defined, measured and reported is required. Level of Evidence: Level IV (Prognostic).

Improvement in the Appearance and Function of the Hand at 2 Weeks after Percutaneous Needle Fasciotomy for Dupuytren Disease.

Background: Percutaneous needle fasciotomy (PNF) has been successfully used for the treatment of contracture bands in the hand in patients with Dupuytren disease. The aim of this study is to determine aesthetic and functional outcomes at 2 weeks following PNF in patients with Dupuytren contracture. Methods: Seventy-five patients undergoing PNF for Dupuytren disease during a 4-month period were included. Patients completed the Visual Analogue Appearance Score (VAAS), Derriford Appearance Score (DAS), and the quick Disabilities of the Arm, Shoulder and Hand score (QuickDASH) preoperatively and at 2 weeks after surgery. In addition, VAAS was done in the immediate postoperative period as well. Results: Seventy-four (99%) patients completed the immediate postoperative VAAS scores and 51 (68%) completed the VAAS, DAS, and QuickDASH at 2 weeks. Preoperative VAAS fell from 6.01 to 1.53 (p < 0.0001) immediately post operation. Two weeks later, VAAS increased to 2.91 but was still significantly lower than preoperatively (p < 0.0001). DAS was unchanged. QuickDASH decreased from 22.4 preoperatively to 12.1 2 weeks later (p = 0.001). Conclusion: PNF for Dupuytren contracture resulted in improvement in both aesthetic and functional outcomes at 2 weeks. Longer term follow-up is required to determine whether these improvements are sustained. Level of Evidence: Level IV (Therapeutic).

Increasing skeletal muscle carnitine content in older individuals increases whole-body fat oxidation during moderate-intensity exercise.

Intramyocellular lipid (IMCL) utilization is impaired in older individuals, and IMCL accumulation is associated with insulin resistance. We hypothesized that increasing muscle total carnitine content in older men would increase fat oxidation and IMCL utilization during exercise, and improve insulin sensitivity. Fourteen healthy older men (69 ± 1 year, BMI 26.5 ± 0.8 kg/m2 ) performed 1 h of cycling at 50% VO2 max and, on a separate occasion, underwent a 60 mU/m2 /min euglycaemic hyperinsulinaemic clamp before and after 25 weeks of daily ingestion of a 220 ml insulinogenic beverage (44.4 g carbohydrate, 13.8 g protein) containing 4.5 g placebo (n = 7) or L-carnitine L-tartrate (n = 7). During supplementation, participants performed twice-weekly cycling for 1 h at 50% VO2 max. Placebo ingestion had no effect on muscle carnitine content or total fat oxidation during exercise at 50% VO2 max. L-carnitine supplementation resulted in a 20% increase in muscle total carnitine content (20.1 ± 1.2 to 23.9 ± 1.7 mmol/kg/dm; p < 0.01) and a 20% increase in total fat oxidation (181.1 ± 15.0 to 220.4 ± 19.6 J/kg lbm/min; p < 0.01), predominantly due to increased IMCL utilization. These changes were associated with increased expression of genes involved in fat metabolism (ACAT1, DGKD & PLIN2; p < 0.05). There was no change in resting insulin-stimulated whole-body or skeletal muscle glucose disposal after supplementation. This is the first study to demonstrate that a carnitine-mediated increase in fat oxidation is achievable in older individuals. This warrants further investigation given reduced lipid turnover is associated with poor metabolic health in older adults.

The association between surgery for carpal and cubital tunnel syndrome: analysis of incidence and risk factors within a geographical area.

The relationship between surgery for cubital tunnel and carpal tunnel syndrome was examined in this retrospective study. Between 1997 and 2018, data from consecutive patients who underwent carpal tunnel release (8352 patients), cubital tunnel release (1681 patients) or both procedures (692 patients) were analysed. The relative risk of undergoing cubital tunnel release in the population who had carpal tunnel release compared with those with no carpal tunnel release was 15.3 (male 20.3; female 12.5). The relative risk of undergoing carpal tunnel release in the population who had cubital tunnel release compared with those who did not undergo carpal tunnel release was 11.5 (male 16.5; female 9.1). Our study showed that men and women who undergo carpal tunnel release are over 20 times and 10 times more likely to have cubital tunnel release than those who did not undergo carpal tunnel release, respectively. These findings suggest that the two conditions may share a similar aetiology.Level of evidence: IV.

The effect of social deprivation on the incidence rate of carpal and cubital tunnel syndrome surgery.

We sought to establish whether carpal and cubital tunnel syndrome requiring surgery is associated with deprivation in England. Data from 10,496 adult patients who were treated in our hand unit over a 20-year period were reviewed. The Index of Multiple Deprivation was used to measure deprivation from the patients' postcode. The mean age at surgery in the most deprived three quintiles was significantly lower than in the least deprived two quintiles for carpal tunnel release (55 vs 59 years, respectively) and cubital tunnel release (52 vs 57 years, respectively). The incidence rate was significantly lower for the three least deprived quintiles when compared with the most deprived quintile for both conditions. The incidence rate ratio of the least deprived quintile compared with the most deprived quintile for carpal tunnel release was 0.70 for men and 0.76 for women. The incidence rate ratio of the least deprived quintile compared with the most deprived quintile for cubital tunnel release was 0.79 for men and 0.49 for women. Carpal tunnel and cubital tunnel syndrome requiring surgery is more common in deprived patients and occurs at an earlier age.Level of evidence: IV.

The effect of the COVID-19 lockdown on hand trauma surgery utilization.

AIMS: The aim of this study was to evaluate the need for hand trauma services during the COVID-19 pandemic lockdown, specifically related to surgical requirements. This will provide useful information for planning and resource allocation in the event of any further lockdown. METHODS: A prospective analsysis of all patients attending our hand trauma unit throughout the UK COVID-19 lockdown period (24 March to 10 May 2020) was carried out. Prospectively collected departmental data from the same period in 2019 was obtained and reviewed for comparison. The number of patients attending clinic, undergoing surgery, the type of surgical procedure, and rate of surgery was compared. RESULTS: In all, 463 patients attended hand trauma services during the lockdown period compared to 793 in 2019 (32% reduction); 190 surgical procedures were carried out during lockdown compared to 236 in 2019 (20% reduction). Intervention rate was higher during the lockdown period (41% compared to 30%). There was no difference in the type of cases. In the first half of lockdown, 47% fewer procedures were performed than in 2019, but in the second half of lockdown 13% more procedures were carried out than the same period in 2019. CONCLUSION: Requirements for hand trauma surgery remain high during a pandemic lockdown. Attendances and surgical requirements can be expected to steadily return to normal levels during a prolonged lockdown period. Throughout any future lockdown period adequate surgical provision must be maintained for patients with hand injuries.Cite this article: Bone Joint Open 2020;1-10:639-643.

Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort.

BACKGROUND: Preschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken. OBJECTIVE: To assess the prevalence of early childhood wheeze across Europe and evaluate risk factors focusing on food allergy, breast feeding and smoke exposure. METHODS: Infants from nine countries were recruited into the EuroPrevall birth cohort. At 12 and 24 months, data on wheeze, allergic signs/symptoms, feeding, smoke exposure, infections and day care attendance were collected using questionnaires. Poisson regression was used to assess risk factors for wheeze. RESULTS: 12 049 infants were recruited. Data from the second year of life were available in 8805 (73.1%). The prevalence of wheeze in the second year of life ranged from <2% in Lodz (Poland) and Vilnius (Lithuania) to 13.1% (95% CI 10.7% to 15.5%) in Southampton (UK) and 17.2% (95% CI 15.0% 19.5%) in Reykjavik (Iceland). In multivariable analysis, frequent lower respiratory tract infections in the first and second years of life (incidence rate ratio (IRR) 1.9 (95% CI 1.3 to 2.6) and 2.5 (95% CI 1.9 to3.4), respectively), postnatal maternal smoking (IRR 1.6, 95% CI 1.1 to 2.4), day care attendance (IRR 1.6, 95% CI 1.1 to 2.5) and male gender (IRR 1.3, 95% CI 1.0 to 1.7) were associated with wheeze. The strength of their association with wheeze differed between countries. Food allergy and breast feeding were not independently associated with wheeze. CONCLUSION: The prevalence of early childhood wheeze varied considerably across Europe. Lower respiratory tract infections, day care attendance, postnatal smoke exposure and male gender are important risk factors. Further research is needed to identify additional modifiable risk factors that may differ between countries.

The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.

U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.

Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients.

BACKGROUND: Cachexia is a consequence of tumor burden caused by ill-defined catabolic alterations in muscle protein turnover. OBJECTIVE: We aimed to explore the effect of tumor burden and resection on muscle protein turnover in patients with nonmetastatic colorectal cancer (CRC), which is a surgically curable tumor that induces cachexia. DESIGN: We recruited the following 2 groups: patients with CRC [n = 13; mean ± SEM age: 66 ± 3 y; BMI (in kg/m(2)): 27.6 ± 1.1] and matched healthy controls (n = 8; age: 71 ± 2 y; BMI: 26.2 ± 1). Control subjects underwent a single study, whereas CRC patients were studied twice before and ~6 wk after surgical resection to assess muscle protein synthesis (MPS), muscle protein breakdown (MPB), and muscle mass by using dual-energy X-ray absorptiometry. RESULTS: Leg muscle mass was lower in CRC patients than in control subjects (6290 ± 456 compared with 7839 ± 617 g; P < 0.05) and had an additional decline after surgery (5840 ± 456 g; P < 0.001). Although postabsorptive MPS was unaffected, catabolic changes with tumor burden included the complete blunting of postprandial MPS (0.038 ± 0.004%/h in the CRC group compared with 0.065 ± 0.006%/h in the control group; P < 0.01) and a trend toward increased MPB under postabsorptive conditions (P = 0.09). Although surgical resection exacerbated muscle atrophy (-7.2%), catabolic changes in protein metabolism had normalized 6 wk after surgery. The recovery in postprandial MPS after surgery was inversely related to the degree of muscle atrophy (r = 0.65, P < 0.01). CONCLUSIONS: CRC patients display reduced postprandial MPS and a trend toward increased MPB, and tumor resection reverses these derangements. With no effective treatment of cancer cachexia, future therapies directed at preserving muscle mass should concentrate on alleviating proteolysis and enhancing anabolic responses to nutrition before surgery while augmenting muscle anabolism after resection.

Muscle protein synthetic responses to exercise: effects of age, volume, and intensity.

We explored the relationships between resistance exercise volume/intensity and muscle myofibrillar protein synthetic (MPS) responses in young and older men. In a crossover design, four groups of six young (24±6 years) and older (70±5 years) men performed two volumes of resistance exercise: either 40% one repetition maximum (1RM) (3 × 14, then 6 × 14 repetitions) or 75% 1RM (3 × 8, then 6 × 8 repetitions), such that at the same volume, work was identical between intensities. Muscle biopsies were taken 0, 1, 2, and 4hours after exercise to measure MPS via myofibrillar bound [1,2-(13)C(2)]leucine and indices of mammalian target of rapamycin signaling by immunoblotting. In younger men, doubling exercise volume produced limited added effects, whereas in older men, it resulted in greater MPS and p70S6 kinase (p70S6K(Thr389)) phosphorylation at both intensities, that is, MPS area under the curve: 75% (1× volume: 0.07±0.01 vs 2× volume: 0.14% ± 0.02% protein synthesized/4hours (p < .001). Doubling exercise volume is a valid strategy to maximize postexercise MPS in ageing.

The influence of carbohydrate-protein co-ingestion following endurance exercise on myofibrillar and mitochondrial protein synthesis.

The aim of the present study was to determine mitochondrial and myofibrillar muscle protein synthesis (MPS) when carbohydrate (CHO) or carbohydrate plus protein (C+P) beverages were ingested following prolonged cycling exercise. The intracellular mechanisms thought to regulate MPS were also investigated. In a single-blind, cross-over study, 10 trained cyclists (age 29 ± 6 years, VO2max 66.5 ± 5.1 ml kg(−1) min(−1)) completed two trials in a randomized order. Subjects cycled for 90 min at 77 ± 1% VO2max before ingesting a CHO (25 g of carbohydrate) or C+P (25 g carbohydrate + 10 g whey protein) beverage immediately and 30 min post-exercise. A primed constant infusion of L-[ring-(13)C6]phenylalanine began 1.5 h prior to exercise and continued until 4 h post-exercise. Muscle biopsy samples were obtained to determine myofibrillar and mitochondrial MPS and the phosphorylation of intracellular signalling proteins. Arterialized blood samples were obtained throughout the protocol. Plasma amino acid and urea concentrations increased following ingestion of C+P only. Serum insulin concentration increased more for C+P than CHO. Myofibrillar MPS was ∼35% greater for C+P compared with CHO (0.087 ± 0.007 and 0.057 ± 0.006% h(−1), respectively; P = 0.025). Mitochondrial MPS rates were similar for C+P and CHO (0.082 ± 0.011 and 0.086 ± 0.018% h(−1), respectively). mTOR(Ser2448) phosphorylation was greater for C+P compared with CHO at 4 h post-exercise (P < 0.05). p70S6K(Thr389) phosphorylation increased at 4 h post-exercise for C+P (P < 0.05), whilst eEF2(Thr56) phosphorylation increased by ∼40% at 4 h post-exercise for CHO only (P < 0.01). The present study demonstrates that the ingestion of protein in addition to carbohydrate stimulates an increase in myofibrillar, but not mitochondrial, MPS following prolonged cycling. These data indicate that the increase in myofibrillar MPS for C+P could, potentially, be mediated through p70S6K, downstream of mTOR, which in turn may suppress the rise in eEF2 on translation elongation.

Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling.

BACKGROUND: We previously showed that human muscle protein synthesis (MPS) increased during infusion of amino acids (AAs) and peaked at ≈120 min before returning to baseline rates, despite elevated plasma AA concentrations. OBJECTIVE: We tested whether a protein meal elicited a similar response and whether signaling responses that regulate messenger RNA translation matched MPS changes. DESIGN: Eight postabsorptive healthy men (≈21 y of age) were studied during 8.5 h of primed continuous infusion of [1,2-¹³C2]leucine with intermittent quadriceps biopsies for determination of MPS and anabolic signaling. After 2.5 h, subjects consumed 48 g whey protein. RESULTS: At 45-90 min after oral protein bolus, mean (± SEM) myofibrillar protein synthesis increased from 0.03 ± 0.003% to 0.10 ± 0.01%/h; thereafter, myofibrillar protein synthesis returned to baseline rates even though plasma essential AA (EAA) concentrations remained elevated (+130% at 120 min, +80% at 180 min). The activity of protein kinase B (PKB) and phosphorylation of eukaryotic initiation factor 4G preceded the rise of MPS and increases in phosphorylation of ribosomal protein kinase S6 (S6K1), and 4E-binding protein 1 (4EBP1) was superimposable with MPS responses until 90 min. However, although MPS decreased thereafter, all signals, with the exception of PKB activity (which mirrored insulin responses), remained elevated, which echoed the slowly declining plasma EAA profile. The phosphorylation of eukaryotic initiation factor 2α increased only at 180 min. Thus, discordance existed between MPS and the mammalian target of rapamycin complex 1 (mTORC1) and signaling (ie, S6K1 and 4EBP1 phosphorylation). CONCLUSIONS: We confirm our previous findings that MPS responses to AAs are transient, even with oral protein bolus. However, changes in MPS only reflect elevated mTORC1 signaling during the upswing in MPS.

Blunting of insulin inhibition of proteolysis in legs of older subjects may contribute to age-related sarcopenia.

BACKGROUND: Reduced postprandial muscle proteolysis is mainly due to increased insulin availability. Whether rates of proteolysis in response to low physiologic doses of insulin are affected by aging is unknown. OBJECTIVES: We tested the hypothesis that suppression of leg protein breakdown (LPB) by insulin is blunted in older subjects, together with blunted activation of Akt-protein kinase B (PKB). DESIGN: Groups of 8 young [mean (+/-SD) age: 24.5 +/- 1.8 y] and older (65.0 +/- 1.3 y) participants were studied during euglycemic (5 mmol/L), isoaminoacidemic (blood leucine approximately 120 micromol/L) clamp procedures at plasma insulin concentrations of approximately 5 and approximately 15 microIU/mL for 1.5 h. Leg amino acid balance, whole-leg protein turnover (as dilution of amino acid tracers), and muscle protein synthesis were measured with D(5)-phenylalanine and [1,2-(13)C(2)]leucine. The kinase activity of muscle Akt-PKB and the extent of phosphorylation of signaling proteins associated with the mTOR (mammalian target of rapamycin) pathway were measured before and after the clamp procedures. RESULTS: Basal LPB rates were not different between groups (66 +/- 11 compared with 51 +/- 10 nmol leucine x 100 mL leg(-1) x min(-1) and 30 +/- 5 compared with 24 +/- 4 nmol phenylalanine x 100 mL leg(-1) x min(-1) in young and older groups, respectively). However, although insulin at approximately 15 microIU/mL lowered LPB by 47% in the young subjects (P < 0.05) and abolished the negative leg amino acid balance, this caused only a 12% fall (P > 0.05) in the older group. Akt-PKB activity mirrored decreases in LPB. No differences were seen in muscle protein synthesis or associated anabolic signaling phosphoproteins. CONCLUSIONS: At moderate availability, the effect of insulin on LPB is diminished in older human beings, and this effect may be mediated through blunted Akt-PKB activation.

Immobilization induces anabolic resistance in human myofibrillar protein synthesis with low and high dose amino acid infusion.

We tested the hypothesis that increasing blood amino acid (AA) availability would counter the physical inactivity-induced reduction in muscle protein synthesis. We determined how 14 days of unilateral knee immobilization affected quadriceps myofibrillar protein synthesis (MPS) in young healthy subjects (10 men, 2 women, 21 +/- 1 years; 80.2 +/- 4.0 kg, mean +/- S.E.M.) in the post-absorptive state and after infusing AA (10% Primene) at low or high doses (43 and 261 mg kg(-1) h(-1)). Muscle cross-sectional area (MRI) and peak isometric torque declined in the immobilized leg (-5.0 +/- 1.2% and -25 +/- 3%, respectively, both P < 0.005), but were unchanged (all P > 0.6) in the non-immobilized leg. Immobilization induced a 27% decline in the rate of post-absorptive MPS (immobilized, 0.027 +/- 0.003: non-immobilized, 0.037 +/- 0.003% h(-1); P < 0.001). Regardless of dose, AA infusion stimulated a greater rise in MPS in the non-immobilized legs; at 4 h MPS was greater by +54 +/- 12% with low dose and +68 +/- 17% with high dose AA infusion (both P < 0.001). There was some evidence of delayed responsiveness of phosphorylation of Akt to high doses of AA and p70S6k at both doses but no marked differences in that of mTOR, GSK3beta or eEF2. Phosphorylation of focal adhesion kinase (Tyr(576/577)) was reduced (P < 0.05) with immobilization. We observed no change in polyubiquitinated protein content after immobilization. We confirm that 14 days of immobilization reduces MPS in the post-absorptive state and this diminution is reduced but not abolished by increased provision of AA, even at high rates. The immobilization-induced decline in post-absorptive MPS with the 'anabolic resistance' to amino acids can account for much of immobilization-induced muscle atrophy.

The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse.

We hypothesized that rates of myofibrillar and patellar tendon collagen synthesis would fall over time during disuse, the changes being accompanied in muscle by decreases in focal adhesion kinase (FAK) phosphorylation and in gene expression for proteolytic enzymes. We studied nine men (22 +/- 4 years, BMI 24 +/- 3 kg m(-2) (means +/- s.d.) who underwent unilateral lower leg suspension for 23 days; five were studied between 0 and 10 days and four between 10 and 21 days. Muscle and tendon biopsies were taken in the postabsorptive state at days 0, 10 and 21 for measurement of protein synthesis, gene expression and protein phosphorylation. Muscle cross-sectional area decreased by 5.2% at 14 days and 10.0% (both P < 0.001), at 23 days, i.e. 0.5% day(-1), whereas tendon dimensions were constant. Rates of myofibrillar protein synthesis fell (P < 0.01) from 0.047% h(-1) at day 0 to 0.022% h(-1) at 10 days without further changes. Tendon collagen synthetic rates also fell (P < 0.01), from 0.052 to 0.023% h(-1) at 10 days and then to 0.010% h(-1) at 21 days. FAK phosphorylation decreased 30% (P < 0.01) at 10 days. No changes occurred in the amounts/phosphorylation of PKB-P70s6k-mTOR pathway components. Expression of mRNA for MuRF-1 increased approximately 3-fold at 10 days without changes in MAFbx or tripeptidyl peptidase II mRNA, but all decreased between 10 and 21 days. Thus, both myofibrillar and tendon protein synthetic rates show progressive decreases during 21 days of disuse; in muscle, this is accompanied by decreased phosphorylation of FAK, with no marked increases in genes for proteolytic enzymes.

Smoking impairs muscle protein synthesis and increases the expression of myostatin and MAFbx in muscle.

Smoking causes multiple organ dysfunction. The effect of smoking on skeletal muscle protein metabolism is unknown. We hypothesized that the rate of skeletal muscle protein synthesis is depressed in smokers compared with non-smokers. We studied eight smokers (> or =20 cigarettes/day for > or =20 years) and eight non-smokers matched for sex (4 men and 4 women per group), age (65 +/- 3 and 63 +/- 3 yr, respectively; means +/- SEM) and body mass index (25.9 +/- 0.9 and 25.1 +/- 1.2 kg/m(2), respectively). Each subject underwent an intravenous infusion of stable isotope-labeled leucine in conjunction with blood and muscle tissue sampling to measure the mixed muscle protein fractional synthesis rate (FSR) and whole body leucine rate of appearance (Ra) in plasma (an index of whole body proteolysis), the expression of genes involved in the regulation of muscle mass (myostatin, a muscle growth inhibitor, and MAFBx and MuRF-1, which encode E3 ubiquitin ligases in the proteasome proteolytic pathway) and that for the inflammatory cytokine TNF-alpha in muscle, and the concentration of inflammatory markers in plasma (C-reactive protein, TNF-alpha, interleukin-6) which are associated with muscle wasting in other conditions. There were no differences between nonsmokers and smokers in plasma leucine concentration, leucine rate of appearance, and plasma concentrations of inflammatory markers, or TNF-alpha mRNA in muscle, but muscle protein FSR was much less (0.037 +/- 0.005 vs. 0.059 +/- 0.005%/h, respectively, P = 0.004), and myostatin and MAFBx (but not MuRF-1) expression were much greater (by approximately 33 and 45%, respectivley, P < 0.05) in the muscle of smokers than of nonsmokers. We conclude that smoking impairs the muscle protein synthesis process and increases the expression of genes associated with impaired muscle maintenance; smoking therefore likely increases the risk of sarcopenia.