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The musculoskeletal system, crucial for movement and support, relies on the delicate balance of connective tissue homeostasis. Maintaining this equilibrium is essential for tissue health and function. There has been increasing evidence in the past decade that shows the circadian clock as a master regulator of extracellular matrix (ECM) homeostasis in several connective tissue clocks. Very recently, exercise has emerged as a significant entrainment factor for cartilage and intervertebral disk circadian rhythms. Understanding the implications of exercise on connective tissue peripheral clocks holds promise for enhancing tissue health and disease prevention. Exercise-induced factors such as heat, glucocorticoid release, mechanical loading, and inter-tissue cross talk may play pivotal roles in entraining the circadian rhythm of connective tissues. This mini review underscores the importance of elucidating the mechanisms through which exercise influences circadian rhythms in connective tissues to optimize ECM homeostasis. Leveraging exercise as a modulator of circadian rhythms in connective tissues may offer novel therapeutic approaches to physical training for preventing musculoskeletal disorders and enhancing recovery.

The myotendinous junction (MTJ), a specialized interface for force transmission between muscle and tendon, has a unique transcriptional activity and is highly susceptible to muscle strain injury. Eccentric exercise training is known to reduce this risk of injury, but knowledge of the influence of exercise on the MTJ at the molecular and cellular levels is limited. In this study, 30 subjects were randomized to a single bout of eccentric exercise 1 week prior to tissue sampling (exercised) or no exercise (control). Samples were collected from the semitendinosus as part of reconstruction of the anterior cruciate ligament and divided into fractions containing muscle, MTJ and tendon, respectively. The concentrations of macrophages and satellite cells were counted, and the expression of genes previously known to be active at the MTJ were analyzed by real-time-quantitative PCR. An effect of the single bout of exercise was found on the expression of nestin (NES) and osteocrin (OSTN) mRNA in the MTJ and tendon fractions. Genes earlier identified at the MTJ (COL22A1, POSTN, ADAMTS8, MNS1, NCAM1) were confirmed to be expressed at a significantly higher level in the MTJ compared to muscle and tendon but were unaffected by exercise. In the exercise group a higher concentration of macrophages, but not of satellite cells, was seen in muscle close to the MTJ. The expression of NES and OSTN was higher in human semitendinosus MTJ 1 week after a single session of heavy eccentric exercise. Based on these results, NES and OSTN could have a part in explaining how the MTJ adapts to eccentric exercise., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Muscle fibre denervation and declining numbers of muscle stem (satellite) cells are defining characteristics of ageing skeletal muscle. The aim of this study was to investigate the potential for lifelong recreational exercise to offset muscle fibre denervation and compromised satellite cell content and function, both at rest and under challenged conditions. Sixteen elderly lifelong recreational exercisers (LLEX) were studied alongside groups of age-matched sedentary (SED) and young subjects. Lean body mass and maximal voluntary contraction were assessed, and a strength training bout was performed. From muscle biopsies, tissue and primary myogenic cell cultures were analysed by immunofluorescence and RT-qPCR to assess myofibre denervation and satellite cell quantity and function. LLEX demonstrated superior muscle function under challenged conditions. When compared with SED, the muscle of LLEX was found to contain a greater content of satellite cells associated with type II myofibres specifically, along with higher mRNA levels of the beta and gamma acetylcholine receptors (AChR). No difference was observed between LLEX and SED for the proportion of denervated fibres or satellite cell function, as assessed in vitro by myogenic cell differentiation and fusion index assays. When compared with inactive counterparts, the skeletal muscle of lifelong exercisers is characterised by greater fatigue resistance under challenged conditions in vivo, together with a more youthful tissue satellite cell and AChR profile. Our data suggest a little recreational level exercise goes a long way in protecting against the emergence of classic phenotypic traits associated with the aged muscle. KEY POINTS: The detrimental effects of ageing can be partially offset by lifelong self-organized recreational exercise, as evidence by preserved type II myofibre-associated satellite cells, a beneficial muscle innervation status and greater fatigue resistance under challenged conditions. Satellite cell function (in vitro), muscle fibre size and muscle fibre denervation determined by immunofluorescence were not affected by recreational exercise. Individuals that are recreationally active are far more abundant than master athletes, which sharply increases the translational perspective of the present study. Future studies should further investigate recreational activity in relation to muscle health, while also including female participants., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The decline in muscle mass and function with age is partly caused by a loss of muscle fibres through denervation. The purpose of this study was to investigate the potential of exercise to influence molecular targets involved in neuromuscular junction (NMJ) stability in healthy elderly individuals. Participants from two studies (one group of 12 young and 12 elderly females and another group of 25 elderly males) performed a unilateral bout of resistance exercise. Muscle biopsies were collected at 4.5 h and up to 7 days post exercise for tissue analysis and cell culture. Molecular targets related to denervation and NMJ stability were analysed by immunohistochemistry and real-time reverse transcription polymerase chain reaction. In addition to a greater presence of denervated fibres, the muscle samples and cultured myotubes from the elderly individuals displayed altered gene expression levels of acetylcholine receptor (AChR) subunits. A single bout of exercise induced general changes in AChR subunit gene expression within the biopsy sampling timeframe, suggesting a sustained plasticity of the NMJ in elderly individuals. These data support the role of exercise in maintaining NMJ stability, even in elderly inactive individuals. Furthermore, the cell culture findings suggest that the transcriptional capacity of satellite cells for AChR subunit genes is negatively affected by ageing.

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term 'older adults' represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. Physical activity is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. Exercise is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults' fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual's physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Advanced glycation end-products (AGEs) accumulate with aging and have been associated with tissue modifications and metabolic disease. Regular exercise has several health benefits, and the purpose of this study was to investigate the effect of regular long-term exercise and diet on skin autofluorescence (SAF) as a measure of glycation and on Achilles tendon structure. In connection with the 2017 European Masters Athletics Championships Stadia, high-level male athletes ( n = 194) that had regularly trained for more than 10 years were recruited, in addition to untrained controls ( n = 34). SAF was non-invasively determined using an AGE Reader. Achilles tendon thickness and vascular Doppler activity were measured by ultrasonography, and diet was assessed by a questionnaire. There was no significant difference in SAF between the athletes and controls. However, greater duration of exercise was independently associated with lower SAF. Diet also had an effect, with a more "Western" diet in youth being associated with increased SAF. Furthermore, our data demonstrated that greater Achilles tendon thickness was associated with aging and training. Together, our data indicate that long-term exercise may yield a modest reduction in glycation and substantially increase Achilles tendon size, which may protect against injury.

Purpose: The discovery of musculoskeletal tissues, including muscle, tendons, and cartilage, as peripheral circadian clocks strongly implicates their role in tissue-specific homeostasis. Age-related dampening and misalignment of the tendon circadian rhythm and its outputs may be responsible for the decline in tendon homeostasis. It is unknown which entrainment signals are responsible for the synchronization of the tendon clock to the light-dark cycle., Methods: We sought to examine any changes in the expression levels of core clock genes (BMAL1, CLOCK, PER2, CRY1, and NR1D1) in healthy human patellar tendon biopsies obtained from three different intervention studies: increased physical activity (leg kicks for 1 h) in young, reduced activity (2 weeks immobilization of one leg) in young, and in old tendons., Results: The expression level of clock genes in human tendon in vivo was very low and a high variation between individuals was found. We were thus unable to detect any differences in core clock gene expression neither after acute exercise nor immobilization., Conclusions: We are unable to find evidence for an effect of exercise or immobilization on circadian clock gene expression in human tendon samples.

The decline in skeletal muscle regenerative capacity with age is partly attributed to muscle stem cell (satellite cell) dysfunction. Recent evidence has pointed to a strong interaction between myoblasts and fibroblasts, but the influence of age on this interaction is unknown. Additionally, while the native tissue environment is known to determine the properties of myogenic cells in vitro, how the aging process alters this cell memory has not been established at the molecular level. We recruited 12 young and 12 elderly women, who performed a single bout of heavy resistance exercise with the knee extensor muscles of one leg. Five days later, muscle biopsies were collected from both legs, and myogenic cells and nonmyogenic cells were isolated for in vitro experiments with mixed or separated cells and analyzed by immunostaining and RT-PCR. A lower myogenic fusion index was detected in the cells from the old versus young women, in association with differences in gene expression levels of key myogenic regulatory factors and senescence, which were further altered by performing exercise before tissue sampling. Coculture with nonmyogenic cells from the elderly led to a higher myogenic differentiation index compared with nonmyogenic cells from the young. These findings show that the in vitro phenotype and molecular profile of human skeletal muscle myoblasts and fibroblasts is determined by the age and exercise state of the original in vivo environment and help explain how exercise can enhance muscle stem cell function in old age.

Purpose: To investigate the effect of blocking the angiotensin II Type I receptor (AT1R) upon the response to acute heavy-resistance exercise in elderly human skeletal muscle. The hypothesis was that AT1R blocking would result in a superior myogenic response accompanied by down-regulation of transforming growth factor-beta and up-regulation of insulin-like growth factor-1 signaling., Methods: Twenty-eight healthy elderly men (+64 yr) were randomized into two groups, consuming either AT1R blocker (losartan, 100 mg·d) or placebo for 18 d before exercise. Participants performed one bout of heavy-unilateral-resistance exercise. Six muscle biopsies were obtained from the vastus lateralis muscles of each subject: two before exercise and four after exercise (4.5 h and 1, 4, and 7 d). Blood pressure and blood samples were collected at the same time points. Biopsies were sectioned for immunohistochemistry to determine the number of satellite cells associated with Type I and Type II fibers. Gene expression levels of Notch, connective tissue, and myogenic signaling pathways were determined by real-time reverse transcription polymerase chain reaction., Results: Changes over time were detected for circulating creatine kinase, the number of satellite cells per Type I fiber, and most of the gene targets, with no specific effect of losartan on these. However, when compared with placebo, losartan intake resulted in a greater suppression of myostatin messenger RNA., Conclusions: In general, there does not seem to be any effect of AT1R blocking on satellite cell number or myogenic pathways in elderly men in the days after one bout of heavy-resistance exercise. However, the greater suppression of myostatin may prove to be beneficial over a long-term intervention designed to induce hypertrophy.

Objective: The aim of this work was to evaluate the time course of changes in strength and functional performance in elderly hospitalized medical patients., Design: This was a prospective observational study in elderly medical patients of age 65 years or older at a geriatric department.Measurements were obtained on days 2 to 4, day 5 to 8, and days 9 to 13. Functional performance was measured with De Morton Mobility Index (DEMMI) test and a 30-second chair stand test (30-s CST). Muscular strength was measured with handgrip strength. Activity level was determined with accelerometry (ActivPAL)., Results: Results in DEMMI and 30-s CST gradually improved (P < 0.05), whereas handgrip strength remained unchanged (P > 0.05). Larger functional improvements were observed in patients with "high" compared to "low" and "moderate" activity level (P < 0.05). Changes in DEMMI score correlated with changes in 30-s CST (P < 0.05); however, changes in DEMMI score and 30-s CST were more likely to occur in patients with a low versus high functional level, respectively., Conclusions: Functional performance of the lower extremities in geriatric patients improves moderately over the time of a hospital stay of less than 14 days, with larger improvements in patients with high activity level. The DEMMI test and the 30-s CST seem to be complementary to each other when evaluating functional changes in a geriatric hospital population., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to (1) describe changes in mobility and muscle strength of geriatric patients during a hospital stay of less than 14 days, (2) understand the significance of physical activity during hospital admission in geriatric patients, and (3) discuss the potential limitations of measures for assessing mobility and lower extremity strength status and change during a hospital admission., Level: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Introduction: Physical and cognitive function decline with age, accelerating during the 6th decade. Loss of muscle power (force×velocity product) is a dominant physical determinant for loss of functional ability, especially if the lower extremities are affected. Muscle strength training is known to maintain or even improve muscle power as well as physical function in older adults, but the optimal type of training for beneficial long-term training effects over several years is unknown. Moreover, the impact of muscle strength training on cognitive function and brain structure remains speculative. The primary aim of this randomised controlled trial is to compare the efficacy of two different 1 year strength training regimens on immediate and long-lasting improvements in muscle power in retirement-age individuals. Secondary aims are to evaluate the effect on muscle strength, muscle mass, physical and cognitive function, mental well-being, health-related quality of life and brain morphology., Methods and Analysis: The study includes 450 home-dwelling men and women (62-70 years). Participants are randomly allocated to (1) 1 year of supervised, centre-based heavy resistance training, (2) home-based moderate intensity resistance training or (3) habitual physical activity (control). Changes in primary (leg extensor power) and secondary outcomes are analysed according to the intention to treat principle and per protocol at 1, 2, 4, 7 and 10 years., Ethics and Dissemination: The study is expected to generate new insights into training-induced promotion of functional ability and independency after retirement and will help to formulate national recommendations regarding physical activity schemes for the growing population of older individuals in western societies. Results will be published in scientific peer-reviewed journals, in PhD theses and at public meetings. The study is approved by the Regional Ethical Committee (Capital Region, Copenhagen, Denmark, number H-3-2014-017)., Trial Registration Number: NCT02123641., Competing Interests: HRS has served on a scientific advisory board for Lundbeck A/S, Valby, Denmark; has received honoraria as speaker from Biogen Idec, Denmark A/S, Genzyme, Denmark, and Merck Serono, Denmark; has received honoraria as editor from Elsevier Publishers, Amsterdam, The Netherlands and Springer Publishing, Stuttgart, Germany; has received travel support from MagVenture, Denmark; and has received a research fund from Biogen Idec, Denmark. The other investigators declare no conflicts of interest. No funders or private companies have any influence on initiation, design, data collection and analysis, publication strategy or management of the study. A data monitoring committee is not needed since the study is investigator driven., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Here, we review the literature on how tendons respond and adapt to ageing and exercise. With respect to aging, there are considerable changes early in life, but this seems to be maturation rather than aging per se. In vitro data indicate that aging is associated with a decreased potential for cell proliferation and a reduction in the number of stem/progenitor-like cells. Further, there is persuasive evidence that turnover in the core of the tendon after maturity is very slow or absent. Tendon fibril diameter, collagen content, and whole tendon size appear to be largely unchanged with aging, while glycation-derived cross-links increase substantially. Mechanically, aging appears to be associated with a reduction in modulus and strength. With respect to exercise, tendon cells respond by producing growth factors, and there is some support for a loading-induced increase in tendon collagen synthesis in humans, which likely reflects synthesis at the very periphery of the tendon rather than the core. Average collagen fibril diameter is largely unaffected by exercise, while there can be some hypertrophy of the whole tendon. In addition, it seems that resistance training can yield increased stiffness and modulus of the tendon and may reduce the amount of glycation. Exercise thereby tends to counteract the effects of aging., (Copyright © 2016 the American Physiological Society.)

Purpose: The elderly lose skeletal muscle mass with age, which may be detrimental for function and quality of life. Both inactivity and heavy resistance exercise are known to have marked but opposite effects upon muscle mass. However, the potential effects of daily physical activity upon muscle protein synthesis (MPS) are less investigated. The aim of this study was to determine the effects of daily physical activities upon MPS in elderly individuals., Methods: A total of 24 elderly men (70±1year) were recruited and randomly assigned: inactivity in form of bed-rest (IA), daily physical activities (DA), or heavy resistance exercise (RE). All groups undertook a normal eating routine containing carbohydrates (52 E%), fat (32 E%), and protein (16 E%). Ingestion of labeled milk protein ([1-(13)C]leucine-labeled whey and caseinate) served to maintain tracer enrichment for determination of 10-hour myofibrillar protein fractional synthesis rates (FSR), and typical prerequisites for calculating FSR were fulfilled. Physical activities were monitored, and venous blood and muscle biopsies collected., Results: Physical activity was highest in the DA compared to both the IA and RE groups. Nutrient ingestion increased insulin, leucine, and phenylalanine plasma concentrations in all groups. [1-(13)C]leucine enrichment was stable throughout the 10-hour FSR period. Myofibrillar protein FSR were similar for IA, DA, and RE groups, 0.055±0.003%/h, 0.058±0.006%/h, and 0.065±0.008%/h, respectively (means±SE, P=0.44)., Conclusions: In elderly males, inactivity, daily activities, and resistance exercise interventions result in equal 10-hour, whole day MPS during an energy- and protein-sufficient diet regimen., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Rheumatoid arthritis (RA) is often associated with diminished muscle mass, reflecting an imbalance between protein synthesis and protein breakdown. To investigate the anabolic potential of both exercise and nutritional protein intake we investigated the muscle protein synthesis rate and anabolic signaling response in patients with RA compared to healthy controls., Methods: Thirteen RA patients (age range 34-84 years; diagnosed for 1-32 years, median 8 years) were individually matched with 13 healthy controls for gender, age, BMI and activity level (CON). Plasma levels of C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using enzyme-linked immunosorbent assay (ELISA) in resting blood samples obtained on two separate days. Skeletal muscle myofibrillar and connective tissue protein fractional synthesis rate (FSR) was measured by incorporation of the amino acid (13)C6-phenylalanine tracer in the overnight fasted state for 3 hours (BASAL) and 3 hours after intake of whey protein (0.5 g/kg lean body mass) alone (PROT, 3 hrs) and in combination with knee-extensor exercise (EX) with one leg (8 × 10 reps at 70 % of 1RM; PROT + EX, 3 hrs). Expression of genes related to inflammatory signaling, myogenesis and muscle growth/atrophy were analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR)., Results: CRP was significantly higher in the RA patients (2.25 (0.50) mg/l) than in controls (1.07 (0.25) mg/l; p = 0.038) and so was TNF-α (RA 1.18 (0.30) pg/ml vs. CON 0.64 (0.07) pg/ml; p = 0.008). Muscle myofibrillar protein synthesis in both RA patients and CON increased in response to PROT and PROT + EX, and even more with PROT + EX (p < 0.001), with no difference between groups (p > 0.05). The gene expression response was largely similar in RA vs. CON, however, expression of the genes coding for TNF-α, myogenin and HGF1 were more responsive to exercise in RA patients than in CON., Conclusions: The study demonstrates that muscle protein synthesis rate and muscle gene expression can be stimulated by protein intake alone and in combination with physical exercise in patients with well-treated RA to a similar extent as in healthy individuals. This indicates that moderately inflamed RA patients have maintained their muscle anabolic responsiveness to physical activity and protein intake.

The musculoskeletal system and its connective tissue include the intramuscular connective tissue, the myotendinous junction, the tendon, the joints with their cartilage and ligaments, and the bone; they all together play a crucial role in maintaining the architecture of the skeletal muscle, ensuring force transmission, storing energy, protecting joint surface and stability, and ensuring the transfer of muscular forces into resulting limb movement. The musculoskeletal connective tissue structure is relatively stable, but mechanical loading and subsequent mechanotransduction and molecular anabolic signaling can result in some adaptation of the connective tissue, its size, its strength, and its mechanical properties, whereby it can improve its capacity by 5-20% with regular physical activity. For several of the mechanically loaded connective tissues, only limited information regarding molecular and cellular signaling pathways and their adaptation to exercise is available. In contrast to tissue responses with exercise, lack of mechanical tissue loading through inactivity or immobilization of the human body will result in a dramatic loss of connective tissue content, structure, and tolerable load within weeks, to a degree (30-40%) that mimics that of contractile skeletal musculature. This illustrates the importance of regular mechanical load in order to preserve the stabilizing role of the connective tissue for the overall function of the musculoskeletal system in both daily activity and exercise., (© 2015 Elsevier Inc. All rights reserved.)

Women differ from men with regard to muscle and tendon, most likely because of sex differences in estrogen. The present experimental findings suggest the hypothesis that estrogen has an anabolic effect on muscle primarily by lowering the protein turnover and enhancing sensitivity to resistance training. Furthermore, estrogen may reduce the stiffness of tendons, an effect that may be modified by physical training.

Purpose: Resistance exercise and amino acid availability are positive regulators of muscle protein net balance (NB). However, anabolic responses to resistance exercise and protein supplementation deserve further elucidation. The purpose was to compare intakes of whey, caseinate (both: 0.30 g/kg lean body mass), or a non-caloric control after heavy resistance exercise on protein turnover and mRNA expressions of forkhead homeobox type O (FOXO) isoforms, muscle RING finger 1 (MuRF1), and Atrogin1 in young healthy males., Methods: Protein turnover was determined by stable isotope-labeled leucine and femoral arteriovenous blood samples at rest and during 6-h recovery. Muscle biopsies were collected at -60 min (rest) and at 60, 210, and 360 min in the recovery period., Results: During recovery, leucine NB was significantly higher in the protein groups compared to control (P < 0.001). Differences in leucine NB, rate of disappearance, and oxidation were observed in the early recovery period between whey and caseinate. FOXO1A and MuRF1 were upregulated at 60 and 210 min, and, in contrast, FOXO3 and Atrogin1 were downregulated at 210 and 360 min. For leucine rate of appearance and all FOXO and atrogene mRNA expressions, no differences were observed between groups., Conclusions: Whey and caseinate were equally superior to control in the 6-h recovery period and displayed temporal differences with whey having a fast and superior effect in the early part of the recovery period. Effects on mRNA expressions indicate different regulatory mechanisms on the ubiquitin ligases MuRF1 and Atrogin1 in recovery from heavy resistance exercise.

Although histology data favour the view of a degenerative nature of tendinopathy, indirect support for inflammatory reactions to loading in affected tendons exists. The purpose of the present study was to elucidate whether inflammatory signalling responses after acute mechanical loading were more pronounced in tendinopathic versus healthy regions of human tendon and if treatment with non-steroidal anti-inflammatory medications (NSAID's) reduces this response. Twenty-seven tendinopathy patients (>6 months) were randomly assigned to a placebo (n = 14) or NSAID (Ibumetin NYCOMED GmbH Plant Oranienburg Germany (600 mg) × 3/day/1 week) group (n = 13) in a double-blinded-fashion. Tendon biopsies were taken from the painful and a healthy region of the same tendon 2 h after 1 h running. Gene-expression of several targets was analysed in the sampled Achilles tendon biopsies. The mRNA for TGF-β, collagen-I and collagen-III were significantly higher expressed, and decorin, CTGF, IL-6 and IL-10 were significantly lower expressed in the tendinopathic versus healthy tendon area. Only IL-10 was lower in expression in experiments with NSAID administration, while all other determined parameters were unaffected by NSAID. All ultrasonographic outcomes were unchanged in response to acute exercise and not influenced by NSAID. The signalling for collagen and TGF-beta was upregulated after acute loading in tendinopathic tendon. In contrast to the hypothesis, inflammatory signalling was not exaggerated in tendinopathic tendon 2 h after acute mechanical loading.

Human bone blood flow and metabolism during physical exercise remains poorly characterized. In the present study we measured femoral bone blood flow and glucose uptake in young healthy subjects by positron emission tomography in three separate protocols. In 6 women, blood flow was measured in femoral bone at rest and during one-leg intermittent isometric exercise with increasing exercise intensities. In 9 men, blood flow in the femur was determined at rest and during dynamic one-leg exercise and two other physiological perturbations: moderate systemic hypoxia (14 O2 ) at rest and during exercise, and during intrafemoral infusion of high-dose adenosine. Bone glucose uptake was measured at rest and during dynamic one-leg exercise in 5 men. The results indicate that isometric exercise increased femoral bone blood flow from rest (1.8 ± 0.6 mL/100 g/min) to low intensity exercise (4.1 ± 1.5 mL/100 g/min, p = 0.01), but blood flow did not increase further with increasing intensity. Resting femoral bone blood flow in men was similar to that of women and dynamic one-leg exercise increased it to 4.2 ± 1.2 mL/100 g/min, p < 0.001. Breathing of hypoxic air did not change femoral bone blood flow at rest or during exercise, but intra-arterial infusion of adenosine during resting conditions increased bone blood flow to 5.7 ± 2.4 mL/100 g/min, to the level of moderate-intensity dynamic exercise. Dynamic one-leg exercise increased femoral bone glucose uptake 4.7-fold compared to resting contralateral leg. In conclusion, resting femoral bone blood flow increases by physical exercise, but appears to level off with increasing exercise intensities. Moreover, although moderate systemic hypoxia does not change bone blood flow at rest or during exercise, intra-arterially administered adenosine during resting conditions is capable of markedly enhancing bone blood flow in humans. Finally, bone glucose uptake also increases substantially in response to exercise., (Copyright © 2013 American Society for Bone and Mineral Research.)

Introduction: We examined short-term (3-hour) and long-term (12-week) training effects after heavy load [HL; 70% 1RM] and light load (LL; 16% 1RM) exercise., Methods: mRNA expression of genes involved in skeletal muscle remodeling were analyzed and muscle activity (EMG measurements) was measured., Results: Relative muscle activity differed between HL and LL resistance exercise, whereas median power frequency was even, suggesting an equal muscle-fiber-type recruitment distribution. mRNA expression of Myf6, myogenin, and p21 was mostly increased, and myostatin was mostly depressed by HL resistance exercise. No major differences were seen in atrophy-related genes between HL and LL resistance exercise. No changes were seen over 12-week training for any of the targets., Conclusions: Resistance exercise at LL and HL elevated the expression of genes involved in skeletal muscle hypertrophy, although the greatest response was from HL. However, no long-term effect from either LL or HL resistance exercise was seen on basal levels of the mRNA targets., (Copyright © 2012 Wiley Periodicals, Inc.)

Background & Aims: Hyperaminoacidemia stimulates myofibrillar fractional synthesis rate (myoFSR) transiently in resting skeletal muscle. We investigated whether light-load resistance exercise can extent this responsiveness., Methods: Ten healthy males exercised one leg with a light-load resistance-like exercise at 16% of 1 repetition maximum and received oral protein boluses every hour for a 10-h period. Their myoFSR was determined by [1-(13)C]-leucine incorporation. Muscle biopsies were obtained from the resting (REST) and exercised (EXC) muscles every 2.5-h in the protein-fed period., Results: Protein feeding significantly elevated plasma leucine and essential amino acids by an average of 39 ± 9% (mean ± SEM) and 20 ± 4%, respectively, compared to the basal concentrations: 197 ± 12 μmol L(-1) and 854 ± 35 μmol L(-1), respectively. The myoFSR was similar in EXC and REST muscles in the first 8 h (all time intervals p > 0.05). After 8 h the myoFSR dropped in the REST muscle to 0.041 ± 0.005%·h(-1), which was 65 ± 5% of the rate in EXC leg at the same time point (0.062 ± 0.004%·h(-1)) and 80 ± 14% of the level in REST leg from 0.5 to 8 h (0.056 ± 0.005%·h(-1)) (interaction p < 0.05)., Conclusions: Compared to rest, light-load exercise prolonged the stimulatory effect of dietary protein on muscle biosynthesis providing perspectives for a muscle restorative effect in clinical settings where strenuous activity is intolerable., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Human connective tissue, e.g., tendon, responds dynamically to physical activity, with collagen synthesis being increased after both acute and prolonged exercise or training. Markers of collagen synthesis and degradation as well as concentration of several potential growth factors have been shown to increase markedly in the peritendinous tissue around the human Achilles tendon following exercise. Of these potential growth factors interleukin-6 (IL-6) showed the largest fold increase, suggesting that IL-6 may be involved in transforming mechanical loading into collagen synthesis in human tendon tissue. In the present study the tissue levels of type I collagen turnover markers [procollagen type I NH(2)-terminal propeptide (PINP) and C-OOH terminal telopeptide of type I collagen (ICTP)] were measured by the use of microdialysis in peritendinous tissue of the Achilles tendon in 14 male volunteers, who had recombinant human IL-6 (rhIL-6) infused into the peritendinous tissue of the Achilles' tendon in one leg, with the other leg serving as control. Subjects were randomly assigned to either a resting group or an exercise group performing a 1-h treadmill run (12 km/h, 2% uphill) before infusion. In addition to IL-6, serum concentrations of collagen turnover markers PINP, ICTP, and COOH-terminal telopeptide of type I collagen (ICTX) were measured. The peritendinous concentration of PINP rose markedly in response to rhIL-6 infusion in both the exercise and the rest group, demonstrating that infusion of IL-6 significantly stimulates collagen synthesis in the peritendinous tissue in humans. Exercise alone did not result in an increased collagen synthesis. This indicates that IL-6 is involved in the collagen synthesis and supports the hypothesis that IL-6 is an important growth factor of the connective tissue in healthy human tendons.

Purpose: The purpose of this study was to determine muscle and tendon protein fractional synthesis rates (FSR) at rest and after a one-legged kicking exercise in patients with knee osteoarthritis (OA) receiving either placebo or nonsteroidal anti-inflammatory drugs (NSAIDs)., Methods: Twenty patients with knee OA (50-70 yr) were enrolled. For each of the 3 days before the exercise intervention, 9 patients were administered NSAIDs (1200 mg), and 11 patients were administered placebo in a double-blinded manner. Each patient performed 60 min of one-legged kicking at 55% of workload maximum while the contralateral leg remained rested. Twenty-four hours after exercise, we determined circulating concentrations of inflammatory parameters and measured FSR of myofibrillar and sarcoplasmic protein fractions of vastus lateralis muscle and patellar tendon collagen protein by the direct incorporation method using a flooding dose of 13C/12C-proline., Results: Circulating levels of prostaglandin F2α were lower in the NSAID group compared with the placebo group (P < 0.05). There was an overall significant effect of exercise on FSR in muscle myofibrillar (P = 0.003) and sarcoplasmic protein (P = 0.026) but not in tendon collagen protein (P = 0.52). No overall significant effect of the drug was seen on either of the tissue protein fractions (P > 0.05) or on the interaction between the drug and exercise on FSR in tendon collagen (P = 0.21), muscle myofibrillar (P = 0.68), or sarcoplasmic protein, FSR (P = 0.16)., Conclusion: In elderly patients with knee OA, an acute bout of moderate exercise significantly increases FSR of muscle myofibrillar and sarcoplasmic protein, but not tendon collagen, 24 h after exercise. NSAID administration in patients with knee OA reduced the level of circulating prostaglandin F2α but did not diminish the exercise-induced response of muscle contractile protein FSR. However, we cannot exclude that a minor inhibition of muscle sarcoplasmic proteins may have been present with NSAID treatment. This study suggests that muscle hypertrophy after long-term training is not influenced by NSAIDs.

Introduction: The microdialysis method was applied to the human knee joint with osteoarthritis (OA) in order to reveal changes in biochemical markers of cartilage and inflammation, intraarticularly and in the synovium, in response to a single bout of mechanical joint loading., Methods: Thirty-one female subjects with OA of the knee were randomized to non-exercise (NEx) or exercise (Ex) groups. Following acute resistance exercise (25 sets of 10 repetitions at 60% of 1 Repetition Maximum) or none (NEx), peripheral nerve blocks just below the inguinal ligament were applied and two microdialysis catheters were positioned in two different compartments, intraarticularly and peri-synovially. The microdialysis catheters were perfused at a slow rate (2 μl/minute) with a solution of Ringer-acetate and radioactively labelled glucose allowing for determination of relative recovery (RR) and calculation of interstitial concentrations of inflammatory and cartilage biomarkers over a three-hour period., Results: A significant increase of Interleukin (IL) -10 was discovered in both positions of the knee in the Ex group over the three hours post exercise, whereas IL-10 remained stationary over time in the NEx group. IL-6 and IL-8 displayed significant increases over time regardless of group and position of the catheter. Cartilage oligomeric matrix protein (COMP) decreased intraarticularly in the post exercise period in the Ex group compared to the NEx group., Conclusions: Exercise caused an increase in both intraarticular and peri-synovial concentrations of IL-10 in a group of human females with knee OA. This suggests a positive effect of exercise on a chondroprotective anti-inflammatory cytokine response in patients with knee OA and might contribute to explaining the beneficial effect that exercise has on OA., Trial Registration: NCT01090375.

Context: The effects of GH on exercise performance remain unclear., Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance., Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment period, they exercised to determine exercise performance and hormonal and metabolic responses., Participants: Twenty healthy males participated in the study., Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed a maximal oxygen uptake (VO(2 max)) test and a prolonged exercise test, consisting of 60 min of submaximal cycling followed by exercise to fatigue at 90% of VO(2 max)., Main Outcome Measures: VO(2 max) was measured before and after the treatment period. Hormonal and metabolic responses and time to exhaustion during prolonged exercise were determined., Results: Resting serum IGF-I concentration decreased by 20% in the GHR antagonist-treated group (P < 0.05), whereas no change was observed in the placebo group. Conversely, resting serum GH concentration was significantly higher in the treatment group compared with the placebo group (P < 0.01). VO(2 max) did not change significantly in either group after the treatment period. Time to exhaustion at 90% of VO(2 max) was significantly shorter in the treatment group (P < 0.05). No significant differences were observed between the groups in terms of changes in serum free fatty acids, glycerol, VO(2), or relative fat oxidation., Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise.

Women are at greater risk than men of sustaining certain kinds of injury and diseases of collagen-rich tissues. To determine whether a high level of oestradiol has an acute influence on collagen synthesis in tendons at rest and in response to exercise, one-legged kicking exercise was performed for 60 min at 67% of maximum power by healthy, young oral contraceptive (OC) users when circulating synthetic (ethinyl) oestradiol was high (n = 11, HE-OC) and compared to similar women who had never used OCs when circulating endogenous oestrogen was low (n = 12, LE-NOC). Interstitial fluid was collected 24 h post-exercise through microdialysis catheters placed anterior to the patellar tendon in both legs and subsequently analysed for the amino-terminal propeptide of type I collagen (PINP), a marker of tendon collagen synthesis. To determine the long-term effect of OC usage, patellar tendon cross-sectional area (CSA) was measured by magnetic resonance imaging (MRI). A lower exercise-induced increase in tendon collagen synthesis was observed in HE-OC than in LE-NOC (DeltaPINP (mean +/- s.e.m.) 1.5 +/- 5.3 versus 24.2 +/- 9.4 ng ml(-1), P < 0.05). Furthermore, serum and the interstitial peritendinous tissue concentrations of insulin-like growth factor I (IGF-I) and IGF-binding proteins showed a reduced bioavailability in HE-OC compared with results in LE-NOC. No difference in patellar tendon CSA was observed between groups. In conclusion, the selective increase in tendon collagen synthesis in LE-NOC but not HE-OC 24 h post-exercise is consistent with the hypothesis that oestradiol inhibits exercise-induced collagen synthesis in human tendon. The mechanism behind this is either a direct effect of oestradiol, or an indirect effect via a reduction in levels of free IGF-I. However, the data did not indicate any long-term effect on tendon size associated with chronic OC use.

Prostaglandins are known to be involved in the regulation of local blood flow within human skeletal muscles during exercise, and the concentration of prostaglandins increases locally and systemically in response to exercise. The systemic release of prostaglandins can be inhibited by oral intake of nonsteroidal anti-inflammatory drugs (NSAIDs). However, to study the local role of prostaglandins, the formation of prostaglandins within the tissue must be controlled. Microdialysis enables determination of local concentrations of water-soluble substances within the tissue. In the present study, the microdialysis method was used to infuse NSAIDs locally into human skeletal muscles producing a local block of prostaglandin formation. In addition, the graded blockade at various distances from the infusion site within the muscle during rest, exercise and recovery was determined. Microdialysis was performed in thigh muscles (vastus lateralis muscle) in six healthy men. One of the microdialysis catheters was used to block prostaglandin synthesis by infusion of the NSAID indomethacin. Additional catheters were placed 1 and 4 cm away from the infusion and in the contralateral leg (working control). Following 2 h of rest, the subjects performed 200 maximal eccentric contractions with each leg followed by 3 h of rest. The study revealed that infusion of NSAID reduced local prostaglandin E(2) concentration by approximately 30-50% (4 cm away from the infusion) and 85% (1 cm away from the infusion) compared with the contralateral (unblocked) thigh muscle. In conclusion, the present study shows that infusion of NSAIDs into human muscle via microdialysis catheters results in a graded blockade of prostaglandin synthesis.

Exercise has been shown to acutely elevate several metabolic processes in tendon tissue, including collagen turnover and blood flow, and chronically induce changes in tendon properties. Many of these acute metabolic responses to exercise are regulated by the cyclooxygenase (COX) enzymes. We measured the expression levels of COX-1 [variants 1 and 2 (COX-1v1 and COX-1v2)], COX-2, and the recently discovered intron 1-retaining COX-1 variants (COX-1b(1), COX-1b(2), and COX-1b(3)) at rest and after resistance exercise (RE). Patellar tendon biopsy samples were taken from six individuals (3 men and 3 women) before and 4 h after a bout of RE (3 sets of 10 repetitions at approximately 70% of 1 repetition maximum) and from a separate group of six individuals (3 men and 3 women) before and 24 h after RE and analyzed by real-time RT-PCR. The COX-1 variants were the most abundant COX mRNAs before exercise and remained unchanged (P > 0.05) after exercise. COX-2 was also expressed in tendon tissue at rest and was unchanged (P > 0.05) after exercise. The intron 1-retaining COX-1 variants were not detectable in tendon tissue before or after exercise. COX-1 and COX-2 were expressed at much higher levels by the patellar tendon than by quadriceps skeletal muscle, although the overall COX mRNA expression patterns were similar in skeletal muscle and tendon (COX-1v2 > COX-1v1, P < 0.05; ratio of COX-1 to COX-2 congruent with 4:1). These results suggest that COX-1 and COX-2 are constitutively expressed at relatively high levels in human patellar tendon and are likely targets of COX-inhibiting drugs at rest and after physical activity.

Evidence from both animal and human studies suggests that adenosine plays a role in the regulation of exercise hyperemia in skeletal muscle. We tested whether adenosine also plays a role in the regulation of blood flow (BF) distribution and heterogeneity among and within quadriceps femoris (QF) muscles during exercise, measured using positron emission tomography. In six healthy young women, BF was measured at rest and then during three incremental low and moderate intermittent isometric one-legged knee-extension exercise intensities without and with theophylline-induced nonselective adenosine receptor blockade. BF heterogeneity within muscles was calculated from 16-mm(3) voxels in BF images and heterogeneity among the muscles from the mean values of the four QF compartments. Mean BF in the whole QF and its four parts increased, and heterogeneity decreased with workload both without and with theophylline (P < 0.001). Adenosine receptor blockade did not have any effect on mean bulk BF or BF heterogeneity among the QF muscles, yet blockade increased within-muscle BF heterogeneity in all four QF muscles (P = 0.03). Taken together, these results show that BF becomes less heterogeneous with increasing exercise intensity in the QF muscle group. Adenosine seems to play a role in muscle BF heterogeneity even in the absence of changes in bulk BF at low and moderate one-leg intermittent isometric exercise intensities.

Introduction: Sedentary behaviour, especially TV viewing, has been identified as a possible risk factor for cardiovascular disease, whereas physical activity seems to protect against major cardiovascular risk factors: obesity, dyslipidemia and hypertension. The aim of this study was to explore the association between both time spent on TV viewing and vigorous intensity physical activity in relation to body mass index, waist circumference, waist/hip ratio, serum lipids and blood pressure., Methods: A total of 1693 men and women, 33-64 years of age, from the 3-year follow-up of a population-based intervention study, The Inter 99 study, were included in this cross-sectional design. Information on TV viewing, physical activity and other lifestyle habits was obtained by self-report questionnaire. Associations between TV viewing/physical activity and biological cardiovascular risk factors were explored by multiple linear regression analyses., Results: Data from 835 (51%) men and 805 (49%) women were included. Mean age was 50.8 years (33.0-64.6). Men had a higher overall physical activity score than women (P<0.0001). TV viewing was significantly, positively associated with waist/hip ratio (P=0.005), body mass index (P=0.03), triglycerides (P=0.005), low density lipoprotein cholesterol (P=0.03), total cholesterol (P=0.01), systolic (P=0.05) and diastolic blood pressure (P=0.03), but not with waist circumference and high density lipoprotein cholesterol (HDL). Engaging in vigorous intensity physical activity was associated with higher HDL (P=0.0006) and lower waist circumference (P<0.0001)., Conclusion: TV viewing and physical activity should be regarded as separate types of behaviour that relate to different cardiovascular disease risk factors.

The consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) is widespread among athletes when faced with muscle soreness or injury, but the effects of NSAIDs on satellite cell activity in humans are unknown. To investigate this, 14 healthy male endurance athletes (mean peak oxygen consumption 62 ml x kg(-1) x min(-1)) volunteered for the study, which involved running 36 km. They were divided into two groups and received either 100 mg indomethacin per day or placebo. Muscle biopsies collected before the run and on days 1, 3, and 8 afterward were analyzed for satellite cells by immunohistochemistry with the aid of neural cell adhesion molecule (NCAM) and fetal antigen-1 (FA1) antibodies. Muscle biopsies were also collected from untrained individuals for comparison. Compared with preexercise levels, a 27% increase in the number of NCAM+ cells was observed on day 8 postexercise in the placebo group (P < 0.05), while levels remained similar at all time points in the NSAID group. No change was seen in the proportion of FA1+ cells, although lower levels were found in the muscle of endurance-trained athletes compared with untrained individuals (P < 0.05). These results suggest that ingestion of anti-inflammatory drugs attenuates the exercise-induced increase in satellite cell number, supporting the role of the cyclooxygenase pathway in satellite cell activity.

Background and Aims: Restricted physical activity as a consequence of chronic disease or injury is a predictor of functional decline. The aim of this study was to test the hypothesis that a 6- month multidimensional training program would have sustained beneficial effects upon the physiological, functional and psychological condition of old women with a recent history of falls., Methods: Participants were 65 home-dwelling women (70-90 years) identified from hospital records as having had an accidental fall. After assessment of muscle strength, balance performance, walking speed, balance confidence, and physical activity level, the participants were randomly assigned to a control group (n=33) or a training group (n=32), who performed a multidimensional training program including moderate resistance exercise and balance exercise twice weekly for 6 months. Measurements were repeated after 6 and 12 months., Results: Six months of multidimensional training resulted in significant improvements and between-group differences in isometric knee extension strength (p<0.05), trunk extension/ flexion strength (p<0.001), habitual/maximal walking speed (p<0.001) and balance performance (p<0.001). At follow-up, 6 months after intervention, these improvements were preserved in the training group and there was also a significant between- group difference with regard to balance confidence. No between-group differences were found concerning number of falls or physical activity level during the one-year study period., Conclusions: A multi-dimensional training program produced significant improvements in physiological and functional risk factors for falls and disability in women aged 70-90 years with a recent history of falls.

Background: Physical activity level and cardiorespiratory fitness are both inversely associated with the risk of cardiovascular diseases and with all-cause mortality. Physical activity questionnaires are often validated against objectively measured maximal oxygen uptake (VO2max)., Aim: To validate a self-report physical activity questionnaire against VO2max and furthermore to establish whether a simple question on self-rated physical fitness could predict objectively measured VO2max., Methods: A total of 102 men and women aged between 35 and 65 years were recruited from an ongoing population-based intervention study, the Inter99 Study. Participants reported their self-rated fitness and daily physical activity using a new questionnaire based on metabolic equivalents (MET). VO2max (ml/kg per min) was determined using a graded bicycle test with increasing workload until exhaustion and with simultaneous measurement of breath-to-breath oxygen uptake in 15-s periods. Statistical analyses were performed by linear regression analyses using the self-reported physical activity level as an independent variable and VO2max (l/min) as an dependent variable, and with covariates sex, age and bodyweight., Results: Data from 53 men and 47 women were analysed. The amount of daily vigorous activity (>6 MET) was significantly positively associated with VO2max (P=0.0001, R=0.76), whereas the total amount of physical activity was not significantly associated with VO2max (P=0.098, R=0.69). A significant trend across three groups of self-rated fitness in relation to VO2max (ml/kg per min) was found (P for trend <0.0001)., Conclusion: The physical activity questionnaire has acceptable validity when compared with VO2max in adult men and women. Furthermore, a simple question on self-rated fitness seems to reflect measured VO2max objectively.

In general, there is a higher incidence of musculoskeletal injuries during physical activity in women than in men. We hypothesized that in women rates of tendon collagen synthesis would be lower than in men at rest and after exercise, especially in the later luteal phase when estrogen and progesterone concentrations are higher than the early follicular phase. We studied tendon collagen fractional synthesis rate (FSR) in 15 young, healthy female subjects in either the early follicular (n = 8) or the late luteal phase (n = 7) 72 h after an acute bout of one-legged exercise (60 min kicking at 67% workload maximum) (72 h) and compared the results with those previously obtained for men. Samples were taken from the patellar tendon in both the exercised and rested legs to determine collagen FSR by the incorporation of [15N]proline into tendon collagen hydroxyproline. There was no effect of menstrual phase on tendon collagen synthesis either at rest or after exercise. However, there was a significant difference between women and men at rest (women = 0.025 +/- 0.002%/h, men = 0.045 +/- 0.008%/h; P < 0.05) and 72 h after exercise (women = 0.027 +/- 0.005%/h; men = 0.058 +/- 0.008%/h). Furthermore, rest and 72-h tendon collagen synthesis were not different in women, whereas in men tendon collagen synthesis remained significantly elevated 72 h after exercise. It is concluded that both in the resting state and after exercise, tendon collagen FSR is lower in women than in men, which may contribute to a lower rate of tissue repair after exercise.

Introduction: In epidemiological studies information on physical activity is often obtained by self-report questionnaires, assessing the type of activities performed, the absolute metabolic demand (metabolic equivalents), and the duration and frequency of the activities. As health benefits from physical activity are coupled to the relative intensity of the physical effort, we wanted to relate perceived exertion to self-reported fitness., Aim: To use a questionnaire for obtaining information on perceived exertion of physical activity in a population sample and to evaluate whether perceived exertion is associated with self-reported fitness., Methods: A total of 42 specific physical activities were included in a perceived exertion questionnaire that was sent by mail to 2,543 randomly selected men and women between 19 and 60 years of age. The participants were asked to rate activities by degree of perceived exertion on an 11-point box-scale. General linear regression analyses were undertaken with perceived exertion of the specific physical activities as outcome variables and age and self-rated fitness as determinants., Results: The response rate was 61.7% (n = 1,568) and 54.3% of the respondents were women. In men and women both, the perceived exertion of 40 out of 42 specific physical activities of low, moderate, and high absolute intensity was negatively associated with self-rated fitness level., Conclusion: Perceived exertion is significantly associated with self-rated fitness level in both genders after adjustment for age. Self-rated fitness level seems to determine perception of exertion in leisure time, occupation, household, and transportation activities, whether of low, moderate, or high absolute intensity.

Background: It is well established that physical activity level is inversely associated with cardiovascular morbidity and mortality, and with all-cause mortality. However, the dose-response relationship between physical activity and other cardiovascular disease risk factors is not fully understood. The aim of the present study was to explore the dose-response relationship between daily physical activity, as measured by a metabolic equivalent score, and BMI, waist circumference, waist hip ratio, total cholesterol, HDL, LDL, triglycerides, systolic and diastolic blood pressure., Methods: A total of 1693 men and women, 33-64 years of age, from the 3 year follow-up of a population-based intervention study, were included in this cross-sectional study. Information on physical activity and other lifestyle factors was obtained by self-report questionnaire. Associations between activity level and biological variables were explored by general linear regression., Results: Data from 835 (51%) men and 805 (49%) women were included. Mean age was 50.8 years (33-64). A significant inverse association between average 24-hour physical activity level < or =45 METs and waist circumference (men p = 0.012, women p = 0.011), BMI (p = 0.0004), waist-hip-ratio (p = 0.002) and triglycerides (p = 0.0001) was found as well as a positive association with HDL (p = <0.0001). In those with an activity level above 45 METs there were no associations. No association was found with total cholesterol, LDL, systolic or diastolic blood pressure., Conclusion: This study suggests a linear dose-response relationship between activity level and certain biological cardiovascular risk factors up to a threshold of a daily 24 h MET-score of 45, which corresponds to a moderate physical activity level.

Microdialysis studies indicate that mechanical loading of human tendon during exercise elevates type I collagen production in tendon. However, the possibility that the insertion of microdialysis fibers per se may increase the local collagen production due to trauma has not been explored. Insulin-like growth factor I (IGF-I) and its binding proteins (IGFBPs), which are known to stimulate collagen production in animal tendons, may regulate the translation of mechanical loading to collagen synthesis. Systemic and tissue levels of IGF-I, IGFBP, and type I collagen metabolism markers [procollagen I COOH-terminal propeptide (PICP) and COOH-terminal telopeptide of type I collagen] were measured by microdialysis in peritendinous tissue of the human Achilles tendon in an exercise group (performing a 36-km run, n = 6) and a control group (no intervention, n = 6). An increase in local PICP concentration was seen in both groups after 72 h and stayed elevated in the exercise group at 96 h (P < 0.05). IGFBP-1 in both serum and dialysate increased in the exercise group immediately after exercise (P < 0.05), whereas IGFBP-3 decreased systemically (P < 0.05). Elevation of local IGFBP-4 was observed in both the control and exercise groups after 48 h (P < 0.05). Total IGF-I did not change in locally or systemically in either group. Our results indicate an increased local production of PICP in human peritendinous tissue in response to prolonged mechanical loading with part of the increase due to trauma from the sampling technique. Care must therefore be emphasized to minimize the numbers of insertions with microdialysis. We demonstrated an elevation of IGFBP-1 both systemically and peritendinously in response to prolonged acute exercise. The local increased collagen synthesis was preceded by an elevation of local concentration of IGFBP-4, suggesting that IGFBP-4 may have a key role in the IGF-axis effect on the human collagen synthesis in vivo.

Major surgery is associated with a decrease in muscle strength, muscle mass and functional performance. However, early intervention with intensive physical training seems to counteract the loss in muscle mass and muscle function as well as to shorten the postoperative length of stay in hospital. In addition, a sufficient intake of protein seems to be a central element in the treatment of postoperative patients to reduce the protein degradation normally seen with immobilisation and surgery. Knowledge regarding the potential effect of preoperative physical activity is sparse.

The extracellular matrix (ECM) of connective tissues enables linking to other tissues, and plays a key role in force transmission and tissue structure maintenance in tendons, ligaments, bone and muscle. ECM turnover is influenced by physical activity, and both collagen synthesis and metalloprotease activity increase with mechanical loading. This can be shown by determining propeptide and proteinase activity by microdialysis, as well as by verifying the incorporation of infused stable isotope amino acids in biopsies. Local tissue expression and release of growth factors for ECM such as IGF-1, TGF-beta and IL-6 is enhanced following exercise. For tendons, metabolic activity (e.g. detected by positron emission tomography scanning), circulatory responses (e.g. as measured by near-infrared spectroscopy and dye dilution) and collagen turnover are markedly increased after exercise. Tendon blood flow is regulated by cyclooxygenase-2 (COX-2)-mediated pathways, and glucose uptake is regulated by specific pathways in tendons that differ from those in skeletal muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as to some degree of net collagen synthesis. These changes modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress-susceptibility and probably make it more load-resistant. The mechanical properties of tendon fascicles vary within a given human tendon, and even show gender differences. The latter is supported by findings of gender-related differences in the activation of collagen synthesis with exercise. These findings may provide the basis for understanding tissue overloading and injury in both tendons and skeletal muscle.

Ageing is associated with a loss in both muscle mass and in the metabolic quality of skeletal muscle. This leads to sarcopenia and reduced daily function, as well as to an increased risk for development of insulin resistance and type 2 diabetes. A major part, but not all, of these changes are associated with an age-related decrease in the physical activity level and can be counteracted by increased physical activity of a resistive nature. Strength training has been shown to improve insulin-stimulated glucose uptake in both healthy elderly individuals and patients with manifest diabetes, and likewise to improve muscle strength in both elderly healthy individuals and in elderly individuals with chronic disease. The increased strength is coupled to improved function and a decreased risk for fall injuries and fractures. Elderly individuals have preserved the capacity to improve muscle strength and mass with training, but seem to display a reduced sensitivity towards stimulating protein synthesis from nutritional intake, rather than by any reduced response in protein turnover to exercise.

Understanding the complex role played by satellite cells in the adaptive response to exercise in human skeletal muscle has just begun. The development of reliable markers for the identification of satellite cell status (quiescence/activation/proliferation) is an important step towards the understanding of satellite cell behaviour in exercised human muscles. It is hypothesised currently that exercise in humans can induce (1) the activation of satellite cells without proliferation, (2) proliferation and withdrawal from differentiation, (3) proliferation and differentiation to provide myonuclei and (4) proliferation and differentiation to generate new muscle fibres or to repair segmental fibre injuries. In humans, the satellite cell pool can increase as early as 4 days following a single bout of exercise and is maintained at higher level following several weeks of training. Cessation of training is associated with a gradual reduction of the previously enhanced satellite cell pool. In the elderly, training counteracts the normal decline in satellite cell number seen with ageing. When the transcriptional activity of existing myonuclei reaches its maximum, daughter cells generated by satellite cell proliferation are involved in protein synthesis by enhancing the number of nuclear domains. Clearly, delineating the events and the mechanisms behind the activation of satellite cells both under physiological and pathological conditions in human skeletal muscles remains an important challenge.

The purpose of this study was to examine the effects of increased fat availability induced by growth hormone (GH) administration on the oxidative metabolism during exercise. Seven well-trained males (age 25 +/- 2 years (mean +/- S.E.M.); peak oxygen consumption : 62 +/- 1 ml min(-1) kg(-1) (completed four randomised trials: 120 min bicycling at 55% 4 h after receiving either 7.5 IU (2.5 mg) GH or placebo (Plc), and during rest after receiving either GH or Plc. In all studies a standardized meal was given 2 h after GH or Plc injection. GH administration resulted in an approximately 60-fold increase in serum GH concentration at rest (P < 0.0001) and during exercise (P < 0.0001). The increase in serum GH was followed by an increase in circulating glycerol at rest (8%, P < 0.0001). When combined with exercise the increase in plasma glycerol was more pronounced (GH: 716% of baseline versus Plc: 328%, P < 0.0001). However, this increase in fat mobilization did not increase fat oxidation during exercise (indirect calorimetry). In conclusion, GH administration combined with aerobic exercise increased lipolytic parameters substantially more than exercise alone, but did not further augment whole body fat oxidation.

We hypothesized that an acute bout of strenuous, non-damaging exercise would increase rates of protein synthesis of collagen in tendon and skeletal muscle but these would be less than those of muscle myofibrillar and sarcoplasmic proteins. Two groups (n = 8 and 6) of healthy young men were studied over 72 h after 1 h of one-legged kicking exercise at 67% of maximum workload (W(max)). To label tissue proteins in muscle and tendon primed, constant infusions of [1-(13)C]leucine or [1-(13)C]valine and flooding doses of [(15)N] or [(13)C]proline were given intravenously, with estimation of labelling in target proteins by gas chromatography-mass spectrometry. Patellar tendon and quadriceps biopsies were taken in exercised and rested legs at 6, 24, 42 or 48 and 72 h after exercise. The fractional synthetic rates of all proteins were elevated at 6 h and rose rapidly to peak at 24 h post exercise (tendon collagen (0.077% h(-1)), muscle collagen (0.054% h(-1)), myofibrillar protein (0.121% h(-1)), and sarcoplasmic protein (0.134% h(-1))). The rates decreased toward basal values by 72 h although rates of tendon collagen and myofibrillar protein synthesis remained elevated. There was no tissue damage of muscle visible on histological evaluation. Neither tissue microdialysate nor serum concentrations of IGF-I and IGF binding proteins (IGFBP-3 and IGFBP-4) or procollagen type I N-terminal propeptide changed from resting values. Thus, there is a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle. The similar time course of changes of protein synthetic rates in different cell types supports the idea of coordinated musculotendinous adaptation.

Under normal healthy conditions, exercise initiates simultaneous elevations in hepatic glucose production (glucose R(a)) and glucose utilisation. As a result, circulating glucose levels are maintained at a relatively constant level. This relatively simple and effective relationship between the liver and the skeletal muscle is maintained by a complex interplay of circulating and locally released neuroendocrine controllers. In large part, exercise-induced changes in the pancreatic secretion of glucagon and insulin are primarily responsible for the stimulation of glucose R(a) during moderate exercise. However, exercise imposed on an additional metabolic stress (heavy exercise and poorly controlled diabetes mellitus) can increase sympathetic drive and has been suggested for decades to play a significant role in glucoregulation. In addition, blood-borne feedback and afferent reflex mechanisms may further modulate the glucose R(a) response to exercise. This article discusses new findings from novel animal and human experiments specifically designed to examine the regulatory components of the neuroendocrine system and their influence on glucoregulation during exercise.

Increases in procollagen processing within skeletal muscle have previously been reported in small animal models only. While indirect measurements in humans have suggested an increase procollagen processing, no intra-skeletal muscle measurements have confirmed these findings. In this study, eight young healthy male subjects performed a single bout of unaccustomed high intensity eccentric exercise on one leg, with the contralateral leg being the control. A significant increase in the muscle interstitial concentration of the N-terminal propeptide of procollagen type I (PINP) was observed (day 0: 1.96 +/- 0.44 ng ml(-1), day 2: 1.94 +/- 0.32 ng ml(-1), day 4: 3.90 +/- 1.03 ng ml(-1), day 8: 7.23 +/- 2.34 ng ml(-1)*, *P < 0.05 vs. basal and control) with no change being noted in the control leg. By day 2 post-exercise, an increase in the histological immunoreactivity of PINP and the N-terminal propeptide of procollagen type III (PIIINP) was also shown in the exercising leg only. Further, from day 2 post-exercise, immunoreactivity for tenascin C and reactive macrophages (CD68+ cells) was seen within the perimysial and endomysial connective tissue of the exercising leg only, indicating a high mechanical load and inflammation. This study shows that following a single bout of high intensity eccentric exercise there is an increase in procollagen processing within skeletal muscle in humans.

No studies to date have reported activation of satellite cells in vivo in human muscle after a single bout of high intensity exercise. In this investigation, eight individuals performed a single bout of high intensity exercise with one leg, the contralateral leg being the control. A significant increase in mononuclear cells staining for the neural cell adhesion molecule (N-CAM) and fetal antigen 1 (FA1) were observed within the exercised human vastus lateralis muscle on days 4 and 8 post exercise. In addition, a significant increase in the concentration of the FA1 protein was determined in intramuscular dialysate samples taken from the vastus lateralis muscle of the exercising leg (day 0: 1.89 +/- 0.82 ng ml(-1); day 2: 1.68 +/- 0.37 ng ml(-1); day 4: 3.26 +/- 1.29 ng ml(-1), P < 0.05 versus basal; day 8: 4.68 +/- 2.06 ng ml(-1), P < 0.05 versus basal and control). No change was noted in the control leg. Despite this increase in N-CAM- and FA1-positive mononuclear cells, an increased expression of myogenin and the neonatal isoform of the myosin heavy chain (MHCn) was not observed. Interestingly, myofibre lesions resulting from extensive damage to the proteins within the myofibre, particularly desmin or dystrophin, were not observed, and hence did not appear to induce the expression of either N-CAM or FA1. We therefore propose that satellite cells can be induced to re-enter the cell growth cycle after a single bout of unaccustomed high intensity exercise. However, a single bout of exercise is not sufficient for the satellite cell to undergo terminal differentiation.