Key PointsQuestionIn adults with overweight or obesity without diabetes, what effect does once-weekly subcutaneous semaglutide, 2.4 mg, have on body weight when added to intensive behavioral therapy with an initial low-calorie diet?FindingsIn this randomized clinical trial that included 611 adults with overweight or obesity, 68 weeks’ treatment with once-weekly subcutaneous semaglutide vs placebo, combined with intensive behavioral therapy (and a low-calorie diet for the initial 8 weeks), resulted in reductions in body weight of 16.0% vs 5.7%, respectively; the difference was statistically significant.MeaningWhen used as an adjunct to intensive behavioral therapy and initial low-calorie diet, once-weekly subcutaneous semaglutide produced significantly greater weight loss than placebo during 68 weeks in adults with overweight or obesity.

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Aim To investigate the effects of once‐weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. Materials and Methods A double‐blind, parallel‐group trial was conducted in 72 adults with obesity, randomized to once‐weekly s.c. semaglutide (dose‐escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant‐reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. Results The area under the concentration–time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC0–5h,para; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non‐significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC0–1h,para, maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration. Ad libitum energy intake was 35% lower with semaglutide versus placebo (1736 versus 2676 kJ; estimated treatment difference −940 kJ; P <0.0001). Semaglutide reduced hunger and prospective food consumption, and increased fullness and satiety when compared with placebo (all P <0.02). The CoEQ indicated better control of eating and fewer/weaker food cravings with semaglutide versus placebo (P <0.05). Body weight was reduced by 9.9% with semaglutide and 0.4% with placebo. Safety was consistent with the known profile of semaglutide. Conclusions In adults with obesity, once‐weekly s.c. semaglutide 2.4 mg suppressed appetite, improved control of eating, and reduced food cravings, ad libitum energy intake and body weight versus placebo. There was no evidence of delayed gastric emptying at week 20, assessed indirectly via paracetamol absorption.

Despite the widespread consumption of nonsteroidal anti-inflammatory drugs (NSAIDs), the influence of these drugs on muscle satellite cells is not fully understood. The aim of the present study was to investigate the effect of a local NSAID infusion on satellite cells after unaccustomed eccentric exercise in vivo in human skeletal muscle. Eight young healthy males performed 200 maximal eccentric contractions with each leg. An NSAID was infused via a microdialysis catheter into the vastus lateralis muscle of one leg (NSAID leg) before, during, and for 4.5 h after exercise, with the other leg working as a control (unblocked leg). Muscle biopsies were collected before and 8 days after exercise. Changes in satellite cells and inflammatory cell numbers were investigated by immunohistochemistry. Satellite cells were identified using antibodies against neural cell adhesion molecule and Pax7. The number of Pax7(+) cells per myofiber was increased by 96% on day 8 after exercise in the unblocked leg (0.14 +/- 0.04, mean +/- SE) compared with the prevalue (0.07 +/- 0.02, P < 0.05), whereas the number of Pax7(+) cells was unchanged in the leg muscles exposed to the NSAID (0.07 +/- 0.01). The number of inflammatory cells (CD68(+) or CD16(+) cells) was not significantly increased in either of the legs 8 days after exercise and was unaffected by the NSAID. The main finding in the present study was that the NSAID infusion for 7.5 h during the exercise day suppressed the exercise-induced increase in the number of satellite cells 8 days after exercise. These results suggest that NSAIDs negatively affect satellite cell activity after unaccustomed eccentric exercise.

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Flyvbjerg A, Langberg H, Kjaer M. Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women. J Appl Physiol 106: 1385-1393, 2009. First published October 16, 2009 doi:10.1152/japplphysiol.90935.2008.-The knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n ϭ 10) or habitual users of oral estradiol replacement therapy (ERT, n ϭ 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH2-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users (P Ͻ 0.001), whereas no group difference was seen in tendon NH2-terminal propeptide of type I collagen synthesis (P ϭ 0.32). In ERT users, positive correlations between serum estradiol (sestradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users (P Ͻ 0.05), whereas the percentage of large fibrils tended to be greater in control (P ϭ 0.10). A lower Young's modulus (GPa/%) was found in ERT users (P Ͻ 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue. connective tissue; tendon fibrils; insulin-like growth factor-I; extracellular matrix; bone CROSS-SECTIONAL FINDINGS INDICATE that sex hormones influence tendon biomechanical properties (36), extracellular matrix adaptability in response to mechanical loading (11,21,36,41,59), and the risk of sustaining soft tissue injuries (11,24,25).Estrogen receptors have been localized in ligaments (32, 33), and tendons express transcripts for estrogen receptors (23). Nevertheless, the effect of estrogen on tendon and ligament turnover is not clarified. Thus an inhibiting effect (34, 60), no effect (51), and a stimulating effect (32) on collagen synthesis and fibroblast proliferation in vitro have been observed in anterior cruciate ligament (ACL) tissue samples. These contrasting findings are probably related to the variation between animal species and the applied methods. This ...

M, Langberg H. Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and muscle connective tissue in young women. J Appl Physiol 106: 1435-1443, 2009. First published October 9, 2008 doi:10.1152/japplphysiol.90933.2008Women are at greater risk than men for certain kinds of diseases and injuries, which may at least partly be caused by sex hormonal differences. We aimed to test the influence of estradiol in vivo on collagen synthesis in tendon, bone, and muscle. Two groups of young, healthy women similar in age, body composition, and exercisetraining status were included. The two groups were either habitual users of oral contraceptives exposed to a high concentration of synthetic estradiol and progestogens (OC, n ϭ 11), or non-OC-users tested in the follicular phase of the menstrual cycle characterized by low concentrations of estradiol and progesterone (control, n ϭ 12). Subjects performed 1 h of one-legged kicking exercise. The next day collagen fractional synthesis rates (FSR) in tendon and muscle connective tissue were measured after a flooding dose of [ 13 C]proline followed by biopsies from the patellar tendon and vastus lateralis in both legs. Simultaneously, microdialysis catheters were inserted in vastus lateralis and in front of the patellar tendon for measurement of insulin-like growth factor I (IGF-I) and its binding proteins. Serum NH 2-terminal propeptide of type I collagen (PINP) and urine COOHterminal telopeptides of type-I collagen (CTX-I) were measured as markers for bone synthesis and breakdown, respectively. Tendon FSR and PINP were lower in OC compared with control. An increase in muscle collagen FSR postexercise was only observed in control (P Ͻ 0.05). Furthermore, the results indicate a lower bioavailability of IGF-I in OC. In conclusion, synthetic female sex hormones administered as OC had an inhibiting effect on collagen synthesis in tendon, bone, and muscle connective tissue, which may be related to a lower bioavailability of IGF-I. estrogen; exercise; insulin-like growth factor I; ethinyl estradiol; bone COLLAGEN is the most abundant protein in the human body and comprises a very high fraction of the tissue organic mass in bone (90%), tendon (60 -85%), ligament (70%), and intramuscular connective tissue (ϳ30% and up to 90%) (31, 57). The frequency of several diseases linked to collagen-rich tissue seems to be biased by sex (30,34,36,65). Furthermore, women are at a greater risk than men for sustaining certain kinds of soft tissue sports injuries (7, 24, 26). Several epidemiological studies have shown that women have up to six times greater risk of anterior cruciate ligament (ACL) ruptures than activity-matched men (24). It has been suggested that sex hormones may influence collagen turnover, tissue composition, and biomechanical properties of the tissues, which in part may explain sex-specific differences in risk (24). In support of this, tendon collagen synthesis is lower in women compared with men at rest and after exercise (47). In addition, a lower p...

Life-long regular endurance exercise is known to counteract the deterioration of cardiovascular and metabolic function and overall mortality. Yet it remains unknown if life-long regular endurance exercise can influence the connective tissue accumulation of advanced glycation endproducts (AGEs) that is associated with aging and lifestyle-related diseases. We therefore examined two groups of healthy elderly men: 15 master athletes (64±4 years) who had been engaged in life-long endurance running and 12 old untrained (66±4 years) together with two groups of healthy young men; ten young athletes matched for running distance (26±4 years), and 12 young untrained (24±3 years). AGE cross-links (pentosidine) of the patellar tendon AGE (2014) were measured biochemically, and in the skin, it was assessed by a fluorometric method. In addition, we determined mechanical properties and microstructure of the patellar tendon. Life-long regular endurance runners (master athletes) had a 21 % lower AGE cross-link density compared to old untrained. Furthermore, both master athletes and young athletes displayed a thicker patellar tendon. These cross-sectional data suggest that life-long regular endurance running can partly counteract the aging process in connective tissue by reducing age-related accumulation of AGEs. This may not only benefit skin and tendon but also other long-lived protein tissues in the body. Furthermore, it appears that endurance running yields tendon tissue hypertrophy that may serve to lower the stress on the tendon and thereby reduce the risk of injury.