GH/IGF-I axis and matrix adaptation of the musculotendinous tissue to exercise in humans.

Exercise is not only associated with adaptive responses within skeletal muscle fibers but also with induction of collagen synthesis both in muscle and adjacent connective tissue. Additionally, exercise and training leads to activation of the systemic growth hormone/insulin-like growth factor I axis (GH/IGF-I), as well as increased local IGF-I expression. Studies in humans with pathologically high levels of GH/IGF-I, and in healthy humans who receive either weeks of GH administration or acute injection of IGF-I into connective tissue, demonstrate increased expression and synthesis of collagen in muscle and tendon. These observations support a stimulatory effect of GH/IGF-I on the connective tissue in muscle and tendon, which appears far more potent than the effect on contractile proteins of skeletal muscle. However, GH/IGF-I may play an additional role in skeletal muscle by regulation of stem cells (satellite cells), as increased satellite cell numbers are found in human muscle with increased GH/IGF-I levels, despite no change in myofibrillar protein synthesis. Although advanced age is associated with both a reduction in the GH/IGF-I axis activity, and in skeletal muscle mass (sarcopenia) as well as in tendon connective tissue, there is no direct proof linking age-related changes in the musculotendinous tissue to an impaired GH/IGF-I axis.

Effect of administration of oral contraceptives on the synthesis and breakdown of myofibrillar proteins in young women.

Oral contraceptive (OC) treatment has an inhibiting effect on protein synthesis in tendon and muscle connective tissue. We aimed to investigate whether OC influence myofibrillar protein turnover in young women. OC-users (24±2 years; Lindynette® n=7, Cilest® n=4) and non-OC-users (controls, 24±4 years n=12) performed one-legged kicking exercise. The next day, the myofibrillar protein fractional synthesis rate (FSR) was measured using stable isotopic tracers ((13)C-proline) while the subjects were fed standardized nutrient drinks. Simultaneously, a marker for myofibrillar protein breakdown, 3-methyl-histidine (3-MH), was measured in the interstitial fluid of the vastus lateralis. Measurements were performed in both legs. In general, myofibrillar protein FSR was lower in OC-users (two-way analysis of variance, P<0.05), although the difference seemed to depend on the OC type. Interstitial 3-MH in the skeletal muscle was not different between groups and did not vary by OC type. Exercise did not change myofibrillar protein FSR or 3-MH concentrations. Serum androstenedione and bioavailability of testosterone were lower in OC-users. In conclusion, the results indicate that the use of OC has an inhibiting effect on myofibrillar protein synthesis and the magnitude of the effect may depend on the type of OC. In contrast, there was no effect of OC on myofibrillar protein breakdown in the fed state.

Myogenic response of human skeletal muscle to 12 weeks of resistance training at light loading intensity.

There is strong evidence for enhanced numbers of satellite cells with heavy resistance training. The satellite cell response to very light muscle loading is, however, unknown. We, therefore, designed a 12-week training protocol where volunteers trained one leg with a high load (H) and the other leg with a light load (L). Twelve young healthy men [mean age 25 ± 3 standard deviation (SD) years] volunteered for the study. Muscle biopsies were collected from the m. vastus lateralis of both legs before and after the training period and satellite cells were visualized by CD56 immunohistochemistry. A significant main effect of time was observed (P<0.001) for the number of CD56+ cells per fiber (L: from 0.11 ± 0.02 to 0.13 ± 0.03; H: from 0.12 ± 0.03 to 0.15 ± 0.05, mean ± SD). The finding that 12 weeks of training skeletal muscle even with very light loads can induce an increase in the number of satellite cells reveals a new aspect of myogenic precursor cell activation and suggests that satellite cells may play a role in skeletal muscle adaptation over a broad physiological range.

Corticosteroid injections, eccentric decline squat training and heavy slow resistance training in patellar tendinopathy.

A randomized-controlled single-blind trial was conducted to investigate the clinical, structural and functional effects of peritendinous corticosteroid injections (CORT), eccentric decline squat training (ECC) and heavy slow resistance training (HSR) in patellar tendinopathy. Thirty-nine male patients were randomized to CORT, ECC or HSR for 12 weeks. We assessed function and symptoms (VISA-p questionnaire), tendon pain during activity (VAS), treatment satisfaction, tendon swelling, tendon vascularization, tendon mechanical properties and collagen crosslink properties. Assessments were made at 0 weeks, 12 weeks and at follow-up (half-year). All groups improved in VISA-p and VAS from 0 to 12 weeks (P<0.05). VISA-p and VAS improvements were maintained at follow-up in ECC and HSR but deteriorated in CORT (P<0.05). In CORT and HSR, tendon swelling decreased (-13+/-9% and -12+/-13%, P<0.05) and so did vascularization (-52+/-49% and -45+/-23%, P<0.01) at 12 weeks. Tendon mechanical properties were similar in healthy and injured tendons and were unaffected by treatment. HSR yielded an elevated collagen network turnover. At the half-year follow-up, treatment satisfaction differed between groups, with HSR being most satisfied. Conclusively, CORT has good short-term but poor long-term clinical effects, in patellar tendinopathy. HSR has good short- and long-term clinical effects accompanied by pathology improvement and increased collagen turnover.

From mechanical loading to collagen synthesis, structural changes and function in human tendon.

The adaptive response of connective tissue to loading requires increased synthesis and turnover of matrix proteins, with special emphasis on collagen. Collagen formation and degradation in the tendon increases with both acute and chronic loading, and data suggest that a gender difference exists, in that females respond less than males with regard to an increase in collagen formation after exercise. It is suggested that estrogen may contribute toward a diminished collagen synthesis response in females. Conversely, the stimulation of collagen synthesis by other growth factors can be shown in both animal and human models where insulin-like growth factor 1 (IGF-I) and transforming growth factor-beta-1 (TGF-beta-1) expression increases to accompany or precede an increase in procollagen expression and collagen synthesis. In humans, it can be demonstrated that an increase in the interstitial concentration of TGF-beta, PGE2, IGF-I plus its binding proteins and interleukin-6 takes place after exercise. The increase in IGF-I expression in tendon includes the isoform that has so far been thought only to exist in skeletal muscle (mechano growth factor). The increase in IGF-I and procollagen expression showed a similar response whether the tendon was stimulated by concentric, isometric or eccentric muscle contraction, suggesting that strain rather that stress/torque determines the collagen-synthesis stimulating response seen with exercise. The adaptation time to chronic loading is longer in tendon tissue compared with contractile elements of skeletal muscle or the heart, and only with very prolonged loading are significant changes in gross dimensions of the tendon observed, suggesting that habitual loading is associated with a robust change in the size and mechanical properties of human tendons. An intimate interplay between mechanical signalling and biochemical changes in the matrix is needed in tendon, such that chemical changes can be converted into adaptations in the morphology, structure and material properties.

Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and muscle connective tissue in young women.

Women 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 exercise-training 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 = 11), or non-OC-users tested in the follicular phase of the menstrual cycle characterized by low concentrations of estradiol and progesterone (control, n = 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 COOH-terminal 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 < 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.

Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity.

Muscle mass accretion is accomplished by heavy-load resistance training. The effect of light-load resistance exercise has been far more sparsely investigated with regard to potential effect on muscle size and contractile strength. We applied a resistance exercise protocol in which the same individual trained one leg at 70% of one-repetition maximum (1RM) (heavy load, HL) while training the other leg at 15.5% 1RM (light load, LL). Eleven sedentary men (age 25 +/- 1 yr) trained for 12 wk at three times/week. Before and after the intervention muscle hypertrophy was determined by magnetic resonance imaging, muscle biopsies were obtained bilaterally from vastus lateralis for determination of myosin heavy chain (MHC) composition, and maximal muscle strength was assessed by 1RM testing and in an isokinetic dynamometer at 60 degrees /s. Quadriceps muscle cross-sectional area increased (P < 0.05) 8 +/- 1% and 3 +/- 1% in HL and LL legs, respectively, with a greater gain in HL than LL (P < 0.05). Likewise, 1RM strength increased (P < 0.001) in both legs (HL: 36 +/- 5%, LL: 19 +/- 2%), albeit more so with HL (P < 0.01). Isokinetic 60 degrees /s muscle strength improved by 13 +/- 5% (P < 0.05) in HL but remained unchanged in LL (4 +/- 5%, not significant). Finally, MHC IIX protein expression was decreased with HL but not LL, despite identical total workload in HL and LL. Our main finding was that LL resistance training was sufficient to induce a small but significant muscle hypertrophy in healthy young men. However, LL resistance training was inferior to HL training in evoking adaptive changes in muscle size and contractile strength and was insufficient to induce changes in MHC composition.

Growth hormone and connective tissue in exercise.

Over the last few years, growth hormone (GH) has become increasingly popular as doping within different sports. However, the precise mechanisms behind the ergogenic (performance enhancing) effects of GH in athletes are still being debated. Besides a well-documented stimulatory effect of GH on carbohydrate and fatty acid metabolism, and a possible anabolic effect on myofibrillar muscle protein, we suggest a role for GH as an anabolic agent in connective tissue in human skeletal muscle and tendon. Given the importance of the connective tissue for the function of skeletal muscle and tendon, a strengthening effect of GH on connective tissue could fit with the ergogenic effect of GH experienced by athletes. This review examines the endogenous secretion of GH and its mediators in relation to exercise. Furthermore, we consider the effect of endogenous GH and administered recombinant human GH (rhGH) on both myofibrillar and connective tissue protein synthesis, thus offering an alternative explanation for the ergogenic effect of GH. Finally, we suggest a possible therapeutic role for rhGH in clinical management of the frequently suffered injuries in the connective tissue.