Acute loading has minor influence on human articular cartilage gene expression and glycosaminoglycan composition in late-stage knee osteoarthritis: a randomised controlled trial.

OBJECTIVE: Osteoarthritis (OA) remains clinically challenging. Regular physical exercise improves symptoms though it is unclear whether exercise influences cartilage at the molecular level. Thus, we aimed to determine the effect of acute loading on gene expression and glycosaminoglycan (GAG) content in human OA cartilage. DESIGN: Patients with primary knee OA participated in this single-blind randomised controlled trial initiated 3.5 h prior to scheduled joint replacement surgery with or without loading by performing one bout of resistance exercise (one-legged leg press). Cartilage from the medial tibia condyle was sampled centrally, under the meniscus, and from peripheral osteophytes. Samples were analysed for gene expression by real-time reverse transcriptase polymerase chain reaction, and hyaluronidase-extracted matrix was analysed for GAG composition by immuno- and dimethyl-methylene blue assays. RESULTS: Of 32 patients randomised, 31 completed the intervention: mean age 69 ± 7.5 years (SD), 58% female, BMI 29.4 ± 4.4 kg/m2. Exercise increased chondroitin sulphate extractability [95% CI: 1.01 to 2.46; P = 0.0486] but cartilage relevant gene expression was unchanged. Regionally, the submeniscal area showed higher MMP-3, MMP-13, IGF-1Ea, and CTGF, together with lower lubricin and COMP expression compared to the central condylar region. Further, osteophyte expression of MMP-1, MMP-13, IGF-1Ea, and TGF-ß3 was higher than articular cartilage and lower for aggrecan, COMP, and FGF-2. Hyaluronidase-extracted matrix from central condylar cartilage contained more GAGs but less chondroitin sulphate compared to submeniscal cartilage. CONCLUSION: Acute exercise had minor influence on cartilage GAG dynamics, indicating that osteoarthritic cartilage is not significantly affected by acute exercise. However, the regional differences suggest a chronic mechanical influence on human cartilage. GOV REGISTRATION NUMBER: NCT03410745.

The regional turnover of cartilage collagen matrix in late-stage human knee osteoarthritis.

OBJECTIVE: Cartilage collagen has very limited repair potential, though some turnover and incorporation has not been fully excluded. We aim to determine the regional turnover of human osteoarthritis cartilage. DESIGN: Patients scheduled for knee joint replacement surgery due to osteoarthritis were recruited in this prospective study of four weeks duration. Deuterium oxide (D2O) was administered orally by weekly boluses at 70% D2O, initially 150 ml followed by three boluses of 50 ml. Cartilage from the medial tibia plateau was sampled centrally, under the meniscus, and from osteophytes and treated enzymatically with hyaluronidase and trypsin. Samples were analysed for deuterium incorporation in alanine using mass spectrometry and for gene expression by real-time reverse transcriptase polymerase chain reaction. RESULTS: Twenty participants completed the study: mean (SD) age 64 ± 9.1 years, 45% female, BMI 29.5 ± 4.8 kg/m2. Enzymatically treated cartilage from central and submeniscal regions showed similar enrichments at 0.063% APE, while osteophytes showed significantly greater enrichment at 0.072% APE (95% confidence interval of difference) [0.004-0.015]). Fractional synthesis rates were similar for central 0.027%/day and submeniscal cartilage 0.022%/day but 10-fold higher in osteophytes 0.22%/day [0.098-0.363]. When compared to central cartilage, submeniscal cartilage had increased gene expression of MMP-3 and decreased lubricin expression. Untreated cartilage had higher turnover (enrichments at 0.073% APE) than enzymatically treated cartilage (0.063% APE). CONCLUSIONS: In OA, despite regional differences in gene expression, the turnover of the articular cartilage matrix across the entire joint surface is very limited, but higher turnover was observed in osteophyte cartilage.

Protective loop-ileostomy in ileal pouch-anal anastomosis for ulcerative colitis - advantages and disadvantages. A retrospective study.

AIM: The aim was to investigate the overall postoperative complication rate within 90 days following ileal pouch-anal anastomosis (IPAA), with or without a diverting stoma, together with complications 30 days after stoma closure and overall pouch failure rate. METHOD: This was a retrospective chart review including IPAA patients with or without a diverting loop-ileostomy for ulcerative colitis (1 January 1983 to 31 December 2015). Demographic data and postoperative complications were retrieved and recorded. RESULTS: A total of 434 patients were included. A diverting loop-ileostomy was performed in 348 patients (80%). Baseline data were similar in the two groups except for body mass index (BMI) and the ratio of women, which were significantly higher in the group without a protective ileostomy. Overall 90-day complication rate after IPAA [Clavien-Dindo (CD) > 2] was similar in the two groups. Clinical anastomotic leaks (CD > 2) were higher in patients without a diverting stoma (9.3% vs 1.7%) (P = 0.002). The odds ratio for leakage after adjustments (age, gender, immune-modulating medicine and BMI) was 5.0 for omitting a diverting stoma (P = 0.004). Complications (CD > 2) after loop-ileostomy closure were seen in 61 cases (14.1%). Omitting a diverting stoma at IPAA demonstrated a non-significant odds ratio of 1.04 (0.46, 2.38) (P = 0.924) for pouch failure after adjustments (age, gender, immune-modulating medicine, BMI, time from pouch formation and clinical leakage). CONCLUSION: The overall postoperative surgical and medical complication rate within 90 days after IPAA was similar in the group with and without diverting stoma. Postoperative complication rate after reversal was 14%. Omitting a diverting stoma at IPAA demonstrated an increased risk of leaks but no significant risk of long-term pouch failure.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis in Denmark: A nationwide cohort study.

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC), and surveillance with ultrasound (US) and alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0-3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI95% 0.4-1.5] in 2002-2003 to 2.9/100 PY [2.4-3.4] in 2012-2013. One-year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP ≥ 20 ng mL-1 was 17%. Twenty-three (21%) patients were diagnosed with early-stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early-stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.

Pouch failures following ileal pouch-anal anastomosis for ulcerative colitis.

AIM: Ileal pouch-anal anastomosis is a procedure offered to patients with ulcerative colitis who opt for restoration of bowel continuity. The aim of this study was to determine the risk of pouch failure and ascertain the risk factors associated with failure. METHOD: The study included 1991 patients with ulcerative colitis who underwent ileal pouch-anal anastomosis in Denmark in the period 1980-2013. Pouch failure was defined as excision of the pouch or presence of an unreversed stoma within 1 year after its creation. We used Cox proportional hazards regression to explore the association between pouch failure and age, gender, synchronous colectomy, primary faecal diversion, annual hospital volume (very low, 1-5 cases per year; low, 6-10; intermediate 11-20; high > 20), calendar year, laparoscopy and primary sclerosing cholangitis. RESULTS: Over a median 11.4 years, 295 failures occurred, corresponding to 5-, 10- and 20-year cumulative risks of 9.1%, 12.1% and 18.2%, respectively. The risk of failure was higher for women [adjusted hazard ratio (aHR) 1.39, 95% CI 1.10-1.75]. Primary non-diversion (aHR 1.63, 95% CI 1.11-2.41) and a low hospital volume (aHR, very low volume vs high volume 2.30, 95% CI 1.26-4.20) were also associated with a higher risk of failure. The risk of failure was not associated with calendar year, primary sclerosing cholangitis, synchronous colectomy or laparoscopy. CONCLUSION: In a cohort of patients from Denmark (where pouch surgery is centralized) with ulcerative colitis and ileal pouch-anal anastomosis, women had a higher risk of pouch failure. Of modifiable factors, low hospital volume and non-diversion were associated with a higher risk of pouch failure.

Factors associated with non-response at health-related quality of life follow-up in a septic shock trial.

BACKGROUND: Follow-up of intensive care unit (ICU) patients often includes health-related quality of life (HRQoL) surveying, but non-responders hamper the interpretation. Our aim was to assess factors for non-response to HRQoL survey in ICU patients with septic shock at follow-up in a clinical trial. METHODS: In a post hoc follow-up registry study, we assessed all the Danish survivors in the Transfusion-Requirements in Septic Shock trial patients, who were mailed the Short Form 36-item Survey (SF-36) 1-year after randomization. We used covariates from the trial database merged with covariates from nation-wide registries using the unique national identification number to explore possible factors for not responding. Five covariates were pre-specified to be included in the primary multivariate analysis: age, number of days in hospital from randomization to follow-up, level of education, cohabitation and employment status at follow-up. We compared the mortality from 1-year survival (2012-2014) till end of final follow-up (January 2016) between non-responders and responders. RESULTS: We assessed 308 survivors of whom 108 (35%) were non-responders. In the primary analysis lower age (odds ratio 1.03, 95% CI [1.01-1.05]), more admission days in hospital (1.006 [1.001-1.011]) and living alone (4.33 [2.46-7.63]) were associated with non-responding, whereas the level of education and employment status were not. Non-responders had a hazard ratio of 1.63 [0.97-2.72] for mortality from 1-year follow-up to final follow-up as compared to the responders. CONCLUSION: Being younger, spending more days in hospital and living alone were all associated with non-response at 1-year HRQoL follow-up among ICU patients with septic shock.

Remodeling of muscle fibers approaching the human myotendinous junction.

The myotendinous junction (MTJ) is at high risk of strain injuries, due to high amounts of energy that is transferred through this structure. The risk of strain injury is significantly reduced by heavy resistance training (HRT), indicating a remodeling capacity of MTJ. We investigated the degree of remodeling of muscle fibers near the human MTJ. In 8 individuals, samples were taken from the semitendinosus and gracilis MTJ and they were stained immunohistochemically for myonuclei (DAPI), fibroblasts (TCF7L2), and satellite cells (CD56). A high portion of the muscle fibers adjacent to the MTJ contained a centrally located myonucleus (47 ± 8%, mean ± SD) and half of the muscle fibers were CD56 positive. The number of satellite cells and fibroblasts were not higher than what has previously been reported from muscle bellies. The immunohistochemical findings suggest that the rate of remodeling of muscle fibers near the MTJ is very high. The finding that there was no increased number of satellite cells and fibroblasts could be explained as a dynamic phenomenon. The effect of HRT should be evaluated in a randomized setting.

In hip osteoarthritis, Nordic Walking is superior to strength training and home-based exercise for improving function.

This observer-blinded, randomized controlled trial compared the short- and long-term effects of 4 months of supervised strength training (ST) in a local fitness center, supervised Nordic Walking (NW) in a local park, and unsupervised home-based exercise (HBE, control) on functional performance in 60+-year-old persons (n = 152) with hip osteoarthritis (OA) not awaiting hip replacement. Functional performance [i.e., 30-s chair stand test (primary outcome), timed stair climbing, and 6-min walk test] and self-reported outcomes (i.e., physical function, pain, physical activity level, self-efficacy, and health-related quality of life) were measured at baseline and at 2, 4, and 12 months. Based on intention-to-treat-analyses improvements [mean (95% CI)] after intervention in number of chair stands were equal in all three groups at 4 months [ST: 0.9 (0.2-1.6), NW: 1.9 (0.8-3.0), HBE: 1.1 (0.1-2.0)] but greater in the NW group [1.4 (0.02-2.8)] than in the ST group at 12 months. Generally, improvements in functional performance were greater (P < 0.001-P < 0.03) after NW compared with HBE and ST at all follow-up time points. Furthermore, NW was superior (P < 0.01) to HBE for improving vigorous physical activity and to both ST and HBE for improving (P < 0.01) mental health. These data suggest that NW is the recommended exercise modality compared with ST and HBE.

Composition and adaptation of human myotendinous junction and neighboring muscle fibers to heavy resistance training.

The myotendinous junction (MTJ) is a common site of strain injury and yet understanding of its composition and ability to adapt to loading is poor. The main aims of this study were to determine the profile of selected collagens and macrophage density in human MTJ and adjoining muscle fibers, and to investigate whether heavy exercise loading would alter this profile. Fifteen individuals scheduled for anterior cruciate ligament repair surgery were randomized into three groups: control, acute or 4 weeks heavy resistance training. MTJ samples were collected from the semitendinosus and gracilis muscles and were sectioned and stained immunohistochemically for collagen types I, III, VI, XII, XIV, XXII, Tenascin-C and CD68. Macrophage density and distribution was evaluated and the amount of each collagen type in muscle and MTJ was graded. Collagen XXII was observed solely at the MTJ, while all other collagens were abundant at the MTJ and in muscle perimysium or endomysium. The endomysial content of collagen XIV, macrophages and Tenascin-C increased following 4 weeks of training. These findings illustrate the heterogeneity of collagen type composition of human MTJ. The increase in collagen XIV following 4 weeks of training may reflect a training-induced protection against strain injuries in this region.

True risk of fetal/neonatal alloimmune thrombocytopenia in subsequent pregnancies: a prospective observational follow-up study.

OBJECTIVES: To assess neonatal platelet counts by comparing alloimmunised pregnancies from a Norwegian screening and intervention study with subsequent pregnancies from the same women. DESIGN: Prospective observational follow-up study. SETTING: A university hospital. POPULATION: HPA-1a immunised women from a large Norwegian screening study that gave birth to one or more children after the screening study ended (2004-2012). METHODS: Follow-up of maternal anti-HPA-1a antibody levels and neonatal platelet counts from the screening pregnancies were compared with subsequent pregnancies. None of the women received antenatal intravenous immunoglobulin (IVIG) treatment and neonatal platelet counts were therefore comparable. MAIN OUTCOME MEASURES: Change in neonatal platelet counts from one HPA-1a incompatible pregnancy to the next. Maternal anti-HPA-a1 antibody levels from one HPA-1a incompatible pregnancy to the next. RESULTS: Forty-five incompatible subsequent pregnancies were identified. Overall, the neonatal platelet count in the subsequent pregnancy was improved (18%), unchanged (52%), or worse (30%), compared with the corresponding screening pregnancy. There was one case of fetal intracranial haemorrhage (ICH) identified in the screening (intrauterine fetal death detected at 30 weeks of gestation) and no ICH cases recorded for the subsequent pregnancies. In cases where the platelet count was lower in the subsequent pregnancy, the maternal anti-HPA-1a antibody level was higher compared with the screening pregnancy. In comparison, the maternal antibody level was lower in subsequent pregnancies where the platelet count improved. CONCLUSIONS: In contrast to what is often stated, we found that the neonatal platelet count was increased or unchanged in the majority of subsequent pregnancies of HPA-1a-immunised women.

Achilles tendon rupture--treatment and complications: a systematic review.

Achilles tendon rupture is a frequent injury with an increasing incidence. Until now, there is no consensus regarding optimal treatment. The aim of this review was to illuminate and summarize randomized controlled trials comparing surgical and non-surgical treatment of Achilles tendon ruptures during the last 10 years. Seven articles were found and they were all acceptable according to international quality assessment guidelines. Primary outcomes were re-ruptures, other complications, and functional outcomes. There was no significant difference in re-ruptures between the two treatments, but a tendency to favoring surgical treatment. Further, one study found an increased risk of soft-tissue-related complications after surgery. Patient satisfaction and time to return to work were significantly different in favor of surgery in one study, and there was also better functional outcome after surgery in some studies. These seven studies indicate that surgical patients have a faster rehabilitation. However, the differences between surgical and non-surgical treatment appear to be subtle and it could mean that rehabilitation is more important, rather than the actual initial treatment. Therefore, further studies will be needed in regard to understanding the interplay between acute surgical or non-surgical treatment, and the rehabilitation regimen for the overall outcome after Achilles tendon ruptures.

The Copenhagen Muscle Research Centre (CMRC) 1994-2004.

This paper presents an impressionistic summary of the formation, activities, accomplishments, and impact of the Copenhagen Muscle Research Centre (CMRC) from 1994 to 2004. The history of the CMRC is viewed in the context of the goals of the original program, the tradition of excellence in exercise physiology in Copenhagen since the time of August Krogh, and the structure of the center. The key role of Professor Bengt Saltin as a visionary, flexible, and inclusive leader is highlighted.

The influence of physical activity during youth on structural and functional properties of the Achilles tendon.

Achilles tendinopathy is a highly prevalent sports injury. Animal studies show a growth response in tendons in response to loading in the immature phase but not after puberty maturation. The aim of this investigation was to examine the structural and material properties in long distance runners who were either physically active (HAY) or inactive (LAY) in young age. Twelve men in HAY group and eight men in LAY group participated. Structural, functional, and biochemical properties of Achilles tendon were estimated from magnetic resonance imaging, ultrasound video recordings, mechanical tests, and tendon biopsies, respectively. There was no difference between the groups with respect to tendon cross-sectional area or tendon free length. There was no difference between the groups with respect to maximal force or mechanical properties. The collagen content, enzymatic and nonenzymatic cross-link density did not differ between the groups, nor did collagen fibril density, diameter, and area. There was a correlation between age and pentosidine/collagen within the groups [(HAY: P < 0.05 and r(2) = 0.47) and (LAY: P < 0.05 and r(2) = 0.52)]. The data suggest that high or low activity during youth did not appreciably influence the mechanical, structural, or biochemical properties of the Achilles tendon in adult long distance runners.

The human myotendinous junction: an ultrastructural and 3D analysis study.

The myotendinous junction (MTJ) is a specialized structure in the musculotendinous system, where force is transmitted from muscle to tendon. Animal models have shown that the MTJ takes form of tendon finger-like processes merging with muscle tissue. The human MTJ is largely unknown and has never been described in three dimensions (3D). The aim of this study was to describe the ultrastructure of the human MTJ and render 3D reconstructions. Fourteen subjects (age 25 ± 3 years) with isolated injury of the anterior cruciate ligament (ACL), scheduled for reconstruction with a semitendinosus/gracilis graft were included. Semitendinosus and gracilis tendons were stripped as grafts for the ACL reconstruction. The MTJ was isolated from the grafts and prepared for transmission electron microscopy (TEM) and focused ion beam/scanning electron microscopy. It was possible to isolate recognizable MTJ tissue from all 14 patients. TEM images displayed similarities to observations in animals: Sarcolemmal evaginations observed as finger-like processes from the tendon and endomysium surrounding the muscle fibers, with myofilaments extending from the final Z-line of the muscle fiber merging with the tendon tissue. The 3D reconstruction revealed that tendon made ridge-like protrusions, which interdigitiated with groove-like indentations in the muscle cell.

Prospective multi-centre randomised trial comparing induction of labour with a double-balloon catheter versus dinoprostone.

This randomised controlled study compared the efficacy of double-balloon catheter versus vaginal prostaglandin E2 (dinoprostone) for induction of labour. In total, 825 pregnant women with cephalic presentation and an unfavourable cervix undergoing induction for conventional indications were randomised to double-balloon or vaginal dinoprostone (3 mg) groups. There was a significantly higher failure rate for labour induction in the balloon group (relative risk: 1.25, 95% confidence interval [CI]: 1.02-1.49). Median induction time was 27.3 h in the balloon group and 29.8 h in the dinoprostone group (difference not significant). After 24 h, 55.3% had given birth in the balloon group versus 54.3% in the dinoprostone group. Additional oxytocin stimulation was used more often in the balloon (46%) compared with that in the dinoprostone (34%) (relative risk: 1.34 (95%CI 1.16 -1.54) group. Caesarean section rates and neonatal outcome were similar. Overall, the two methods for induction were comparable with regard to efficacy and safety.

Lower basal and postprandial muscle protein synthesis after 2 weeks single-leg immobilization in older men: No protective effect of anti-inflammatory medication.

Muscle inactivity may reduce basal and postprandial muscle protein synthesis (MPS) rates in humans. Anti-inflammatory treatment alleviates the MPS impairments in younger individuals. The present study explored the influence of nonsteroidal anti-inflammatory drugs (NSAIDs) upon MPS during a period of inactivity in older humans. Eighteen men (age 60-80 years) were allocated to ibuprofen (1200 mg/day, Ibu) or control (Plc) groups. One lower limb was cast immobilized for 2 weeks. Postabsorptive and postprandial MPS was measured before and after the immobilization by L-[ring-13 C6 ]-phenylalanine infusion. The protein expression of select anabolic signaling molecules was investigated by western blot. Basal (0.038 ± 0.002%/h and 0.039 ± 0.005%/h, Plc and Ibu, respectively) and postprandial (0.064 ± 0.004%/h and 0.067 ± 0.010%/h, Plc and Ibu, respectively) MPS rate were higher pre-immobilization compared to basal (0.019 ± 0.005%/h and 0.020 ± 0.010%/h, Plc and Ibu, respectively) and postprandial (0.033 ± 0.005%/h and 0.037 ± 0.006%/h, Plc and Ibu, respectively) MPS rate post-immobilization (p < 0.001). NSAID treatment did not affect the suppression of MPS (p > 0.05). The anabolic signaling were in general reduced after immobilization (p < 0.05). These changes were unaffected by NSAID treatment (p > 0.05). Basal and postprandial MPS dropped markedly after 2 weeks of lower limb immobilization. NSAID treatment neither influenced the reduction in MPS nor the anabolic signaling after immobilization in healthy older individuals.

Tendon and skeletal muscle matrix gene expression and functional responses to immobilisation and rehabilitation in young males: effect of growth hormone administration.

We examined the effect of growth hormone (GH) on connective tissue of tendon and skeletal muscle during immobilisation and re-training in humans. Young men (20-30 years; n = 20) were randomly assigned to daily recombinant human GH (rhGH) (33-50 µg kg(-1) day(-1)) or placebo (Plc), and had one leg immobilised for 2 weeks, followed by 6 weeks of strength training. The cross-sectional area (CSA), maximal muscle strength (maximal voluntary contraction, MVC) and biomechanical properties of the quadriceps muscle and patellar tendon were determined. Muscle and tendon biopsies were analysed for mRNA of collagen (COL1A1/3A1), insulin-like growth factors (IGF-1Ea/Ec), lysyl oxidase (LOX), matrix metalloproteases (MMP-2 and MMP-9), decorin and tenascin-C. Fibril morphology was analysed by transmission electron microscopy (TEM) to detect changes in the fibril diameter distribution. In muscle, CSA and MVC declined with immobilisation and recovered with rehabilitation similarly in both groups. Likewise, both groups showed increased IGF-1Ea/Ec and COL1A1/3A1 expression in muscle during re-training after immobilisation compared with baseline, and the increase was more pronounced when subjects received GH. The tendon CSA did not change during immobilisation, but increased in both groups during 6 weeks of rehabilitation (∼14%). A decline in tendon stiffness after immobilisation was observed only in the Plc group, and an increase during 6 weeks of rehabilitation was observed only in the GH group. IGF-1Ea and COL1A1/3A1 mRNA increased with immobilisation in the GH group only, and LOX mRNA was higher in the GH group than in the Plc group after immobilisation. Both groups showed an increase in MMP-2 with immobilisation, whereas no changes in MMP-9, decorin and tenascin-C were observed. The tendon fibril diameter distribution remained unchanged in both groups. In conclusion, GH stimulates collagen expression in both skeletal muscle and tendon, abolishes the normal inactivity-related decline in tendon stiffness and LOX, and results in increased tendon CSA and stiffness during rehabilitation. GH has a matrix-stabilising effect during periods of inactivity and rehabilitation in humans.

Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle.

Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61-74 yrs) and 11 young (YM: mean age 24.4, range 21-30 yrs) males. Measures of myofibre area (MFA), Pax7-positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7-positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7-positive cells, and had more Pax7-positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age-related differences were observed in mRNA expression of IGF-1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down-regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age-related difference in muscle mass recovery.

Local administration of insulin-like growth factor-I (IGF-I) stimulates tendon collagen synthesis in humans.

Collagen is the predominant structural protein in tendons and ligaments, and can be controlled by hormonal changes. In animals, injections of insulin-like growth factor I (IGF-I) has been shown to increase collagen synthesis in tendons and ligaments and to improve structural tissue healing, but the effect of local IGF-I administration on tendon collagen synthesis in human has not been studied. The purpose of this study was to study whether local injections of IGF-I would have a stimulating effect on tendon collagen synthesis. Twelve healthy nonsmoking men [age 62 ± 1 years (mean ± SEM), BMI 27 ± 1] participated. Two injections of either human recombinant IGF-I (0.1 mL Increlex©) or saline (control) into each patellar tendon were performed 24-h apart, respectively. Tendon collagen fractional synthesis rate (FSR) was measured by stable isotope technique in the hours after the second injection. Simultaneously, interstitial peritendinous (IGF-I) and [procollagen type I N-terminal propeptide (PINP)], as a marker for type I collagen synthesis, were determined by microdialysis technique. Tendon collagen FSR and PINP were significantly higher in the IGF-I leg compared with the control leg (P < 0.05). In conclusion, local IGF-I administration can directly enhance tendon collagen synthesis both within and around the human tendon tissue.