Regional regulation of focal adhesion kinase after concentric and eccentric loading is related to remodelling of human skeletal muscle.

AIMS: We assessed focal adhesion kinase (FAK) response to concentric (CON) vs eccentric (ECC) resistance training (RT) at two vastus lateralis (VL) sites, and the relationships between FAK, muscle protein synthesis (MPS) and morphological remodelling. METHODS: Six young males trained both legs unilaterally 3 times/week for 8 weeks; one leg performed CON RT, the contralateral performed ECC RT. Muscle biopsies were collected after training from VL mid-belly (MID) and distal (distal) sites at 0, 4, 8 weeks. Focal adhesion kinase content and activation were evaluated by immunoblotting. MPS was assessed by deuterium oxide tracer; morphological adaptations were evaluated by ultrasound and DXA. RESULTS: pY397-FAK 8 weeks levels were ~4-fold greater after ECC at the distal site compared to CON (P < .05); pY397FAK to total FAK ratio was greater in ECC vs CON at 4 (~2.2-fold, P < .05) and 8 weeks (~9-fold, P < .001) at the distal site. Meta-vinculin was found transiently increased at 4 weeks at the distal site only after ECC RT. ECC presented greater fascicle length (Lf) increases (10.5% vs 4%), whereas CON showed greater in pennation angle (PA) changes (12.3% vs 2.1%). MPS did not differ between exercise types or muscle sites at all time points. distal pY397-FAK and pY397-FAK/FAK values correlated to changes in Lf at 8 weeks (r = .76, P < .01 and r = .66, P < .05 respectively). CONCLUSION: Focal adhesion kinase phosphorylation was greater at 8 weeks after ECC RT and was muscle region-specific. FAK activity correlated to contraction-dependent architectural remodelling, suggesting a potential role of FAK in orienting muscle structural changes in response to distinct mechanical stimuli.

The effect of body composition and serum inflammatory markers on the functional muscle-bone unit in premenopausal women.

BACKGROUND/OBJECTIVES: A number of recent studies dealing with the relationship between the effects of high body mass (BM) and fat mass (FM) on bone mass and strength exhibit a range of contrasting variations in their findings. These diverse findings have led to an ongoing controversy as to whether high BM and FM positively or negatively affect bone mass and strength. Excessive FM and the associated low-grade inflammation might overturn the higher mechanical stimulus arising from a higher BM. Therefore, we aimed at quantifying the functional muscle-bone unit in premenopausal women with markedly diverging body composition. SUBJECTS/METHODS: Sixty-four young women with BMs ranging from 50 to 113 kg and body fat percentages between 20.7% and 51.8% underwent jumping mechanography and peripheral quantitative computed tomography measurements. Maximum voluntary ground reaction force during multiple one-legged hopping (Fm1LH), as well as bone characteristics at 4, 14 and 38% of tibia length, were determined. Body composition was assessed by dual-energy X-ray absorptiometry, and serum inflammatory markers were analyzed from blood samples. RESULTS: Fm1LH predicted volumetric bone mineral content at the 14% site by 48.7%. Women with high body fat percentage had significantly higher Fm1LH, significantly lower relative bone mass, relative bone strength and relative bone area, as well as higher serum inflammatory markers in comparison to women with lower body fat percentage. CONCLUSIONS: In conclusion, high body fat percentage was associated with lower relative bone mass and strength despite normal habitual muscle force in premenopausal women, indicating that high body fat percentage compromised the functional muscle-bone unit in these individuals.

Physiological, biochemical, anthropometric, and biomechanical influences on exercise economy in humans.

Interindividual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 healthy males (VO2 max range 45.5-72.1 mL·min-1 ·kg-1 ), no factor related to skeletal muscle structure (% slow-twitch fiber content, number of capillaries per fiber), mitochondrial properties (volume density, oxidative capacity, or mitochondrial efficiency), or protein content (UCP3 and MFN2 expression) explained variation in cycling and running EE among subjects. In contrast, biomechanical variables related to vertical displacement correlated well with running EE, but were not significant when taking body weight into account. Thus, running EE and body weight were correlated (R2 =.94; P<.001), but was lower for cycling EE (R2 =.23; P<.023). To separate biomechanical determinants of running EE, we contrasted individual running and cycling EE considering that during cycle ergometer exercise, the biomechanical influence on EE would be small because of the fixed movement pattern. Differences in cycling and running exercise protocols, for example, related to biomechanics, play however only a secondary role in determining EE. There was no evidence for an impact of structural or functional skeletal muscle variables on EE. Body weight was the main determinant of EE explaining 94% of variance in running EE, although more than 50% of the variability of cycling EE remains unexplained.

Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study.

Background: Vemurafenib has shown activity in patients with BRAFV600 mutated melanoma with brain metastases (BM). This phase 2 study evaluated vemurafenib in patients with/without prior treatment for BM. Methods: Patients with BRAFV600 mutated melanoma with BM were enrolled into cohort 1 (previously untreated BM) and cohort 2 (previously treated BM) and received vemurafenib (960 mg BID) until disease progression (PD) or intolerance. Primary endpoint was best overall response rate (BORR) in the brain in cohort 1 that was evaluated using modified RECIST 1.1 criteria using lesions ≥0.5 cm to assess response. Results: 146 patients were treated (cohort 1 n = 90; cohort 2 n = 56), 62% of whom were male. Median (range) time since diagnosis of BM: 1.0 (0-9) month in cohort 1 and 4.2 (1-68) months in cohort 2. Median duration of treatment was 4.1 months (range 0.3-34.5) in cohort 1 and 4.1 months (range 0.2-27.6) in cohort 2. Intracranial BORR in cohort 1 by an independent review committee (IRC) was 18% (2 CRs, 14 PRs). Extracranial BORR by IRC was 33% in cohort 1 and 23% in cohort 2. Median PFS (brain only, investigator-assessed) was 3.7 months (range 0.03-33.4; IQR 1.9-5.6) in cohort 1 and 4.0 months (range 0.3-27.4; IQR 2.2-7.4) in cohort 2. Median OS was 8.9 months (range 0.6-34.5; IQR 4.9-17.0) in cohort 1 and 9.6 months (range 0.7-34.3; IQR 4.5-18.4) in cohort 2. Adverse events (AEs) were similar in type, grade and frequency to other studies of single-agent vemurafenib. Grade 3/4 AEs occurred in 59 (66%) patients in cohort 1 and 36 (64%) in cohort 2. Overall, 84% of patients died during the study (86% in cohort 1 and 80% in cohort 2), mainly due to disease progression. Conclusions: The study demonstrates clinically meaningful response rates of melanoma BM to vemurafenib, which was well tolerated and without significant CNS toxicity.

ACE inhibition modifies exercise-induced pro-angiogenic and mitochondrial gene transcript expression.

Skeletal muscle responds to endurance exercise with an improvement of biochemical pathways that support substrate supply and oxygen-dependent metabolism. This is reflected by enhanced expression of associated factors after exercise and is specifically modulated by tissue perfusion and oxygenation. We hypothesized that transcript expression of pro-angiogenic factors (VEGF, tenascin-C, Angpt1, Angpt1R) and oxygen metabolism (COX4I1, COX4I2, HIF-1α) in human muscle after an endurance stimulus depends on vasoconstriction, and would be modulated through angiotensin-converting enzyme inhibition by intake of lisinopril. Fourteen non-specifically trained, male Caucasians subjects, carried out a single bout of standardized one-legged bicycle exercise. Seven of the participants consumed lisinopril in the 3 days before exercise. Biopsies were collected pre- and 3 h post-exercise from the m. vastus lateralis. COX4I1 (P = 0.03), COX4I2 (P = 0.04) mRNA and HIF-1α (P = 0.05) mRNA and protein levels (P = 0.01) showed an exercise-induced increase in the group not consuming the ACE inhibitor. Conversely, there was a specific exercise-induced increase in VEGF transcript (P = 0.04) and protein levels (P = 0.03) and a trend for increased tenascin-c transcript levels (P = 0.09) for subjects consuming lisinopril. The observations indicate that exercise-induced expression of transcripts involved in angiogenesis and mitochondrial energy metabolism are to some extent regulated via a hypoxia-related ACE-dependent mechanism.

Protective effect of focal adhesion kinase against skeletal muscle reperfusion injury after acute limb ischemia.

OBJECTIVES: In cardiac muscle, ischemia reperfusion (IR) injury is attenuated by mitochondrial function, which may be upregulated by focal adhesion kinase (FAK). The aim of this study was to determine whether increased FAK levels reduced rhabdomyolysis in skeletal muscle too. MATERIAL AND METHODS: In a translational in vivo experiment, rat lower limbs were subjected to 4 hours of ischemia followed by 24 or 72 hours of reperfusion. FAK expression was stimulated 7 days before (via somatic transfection with pCMV-driven FAK expression plasmid) and outcomes were measured against non-transfected and empty transfected controls. Slow oxidative (i.e., mitochondria-rich) and fast glycolytic (i.e., mitochondria-poor) type muscles were analyzed separately regarding rhabdomyolysis, apoptosis, and inflammation. Severity of IR injury was assessed using paired non-ischemic controls. RESULTS: After 24 hours of reperfusion, marked rhabdomyolysis was found in non-transfected and empty plasmid-transfected fast-type glycolytic muscle, tibialis anterior. Prior transfection enhanced FAK concentration significantly (p = 0.01). Concomitantly, levels of BAX, promoting mitochondrial transition pores, were reduced sixfold (p = 0.02) together with a blunted inflammation (p = 0.01) and reduced rhabdomyolysis (p = 0.003). Slow oxidative muscle, m. soleus, reacted differently: although apoptosis was detectable after IR, rhabdomyolysis did not appear before 72 hours of reperfusion; and FAK levels were not enhanced in ischemic muscle despite transfection (p = 0.66). CONCLUSIONS: IR-induced skeletal muscle rhabdomyolysis is a fiber type-specific phenomenon that appears to be modulated by mitochondria reserves. Stimulation of FAK may exploit these reserves constituting a potential therapeutic approach to reduce tissue loss following acute limb IR in fast-type muscle.

Adjustments of muscle capillarity but not mitochondrial protein with skiing in the elderly.

Downhill skiing in the elderly increases maximal oxygen uptake (VO2max) and carbohydrate handling, and produces muscle hypertrophy. We hypothesized that adjustments of the cellular components of aerobic glucose combustion in knee extensor muscle, and cardiovascular adjustments, would increase in proportion to VO2max. Nineteen healthy elderly subjects (age 67.5 ± 2.9 years) who completed 28.5 days of guided downhill skiing over 3 months were assessed for anthropometric variables, cardiovascular parameters (heart rate, hematocrit), VO2max, and compared with controls (n = 20). Biopsies of vastus lateralis muscle were analyzed for capillary density and expression of respiratory chain markers (NDUFA9, SDHA, UQCRC1, ATP5A1) and the glucose transporter GLUT4. Statistical significance was assessed with a repeated analysis of variance and Fisher's post-hoc test at a P value of 5%. VO2max increased selectively with ski training (+7 ± 2%). Capillary density (+11 ± 5%) and capillary-to-fiber ratio (12 ± 5%), but not the concentration of metabolic proteins, in vastus lateralis were increased after skiing. Cardiovascular parameters did not change. Fold changes in VO2max and capillary-to-fiber ratio were correlated and were under genetic control by polymorphisms of the regulator of vascular tone, angiotensin converting enzyme. The observations indicate that increased VO2max after recreational downhill ski training is associated with improved capillarity in a mainly recruited muscle group.

A lifting line model to investigate the influence of tip feathers on wing performance.

Bird wings have been studied as prototypes for wing design since the beginning of aviation. Although wing tip slots, i.e. wings with distinct gaps between the tip feathers (primaries), are very common in many birds, only a few studies have been conducted on the benefits of tip feathers on the wing's performance, and the aerodynamics behind tip feathers remains to be understood. Consequently most aircraft do not yet copy this feature. To close this knowledge gap an extended lifting line model was created to calculate the lift distribution and drag of wings with tip feathers. With this model, is was easily possible to combine several lifting surfaces into various different birdwing-like configurations. By including viscous drag effects, good agreement with an experimental tip slotted reference case was achieved. Implemented in C++ this model resulted in computation times of less than one minute per wing configuration on a standard notebook computer. Thus it was possible to analyse the performance of over 100 different wing configurations with and without tip feathers. While generally an increase in wing efficiency was obtained by splitting a wing tip into distinct, feather-like winglets, the best performance was generally found when spreading more feathers over a larger dihedral angle out of the wing plane. However, as the results were very sensitive to the precise geometry of the feather fan (especially feather twist) a careless set-up could just as easily degrade performance. Hence a detailed optimization is recommended to realize the full benefits by simultaneously optimizing feather sweep, twist and dihedral angles.

Architectural, functional and molecular responses to concentric and eccentric loading in human skeletal muscle.

AIM: We investigated architectural, functional and molecular responses of human skeletal muscle to concentric (CON) or eccentric (ECC) resistance training (RT). METHODS: Twelve young males performed 10 weeks of concentric (CON) or eccentric (ECC) resistance training (RT) (n = 6 CON, 6 ECC). An additional 14 males were recruited to evaluate acute muscle fascicle behaviour and molecular signalling in biopsies collected from vastus lateralis (VL) after 30 min of single bouts of CON or ECC exercise. VL volume was measured by magnetic resonance imaging. Muscle architecture (fascicle length, Lf; pennation angle, PA) was evaluated by ultrasonography. Muscle remodelling signals to CON or ECC loading [MAPK/AKT-mammalian target of rapamycin (mTOR) signalling] and inflammatory pathway (TNFαMurf-1-MAFbx) were evaluated by immunoblotting. RESULTS: Despite the ~1.2-fold greater load of the ECC group, similar increases in muscle volume (+8% CON and +6% ECC) and in maximal voluntary isometric contraction (+9% CON and +11% ECC) were found after RT. However, increases in Lf were greater after ECC than CON (+12 vs. +5%) while increases in PA were greater in CON than ECC (+30 vs. +5%). Distinct architectural adaptations were associated with preferential growth in the distal regions of VL for ECC (+ECC +8% vs. +CON +2) and mid belly for CON (ECC +7 vs. CON +11%). While MAPK activation (p38MAPK, ERK1/2, p90RSK) was specific to ECC, neither mode affected AKT-mTOR or inflammatory signalling 30 min after exercise. CONCLUSION: Muscle growth with CON and ECC RT occurs with different morphological adaptations reflecting distinct fibre fascicle behaviour and molecular responses.

Regulatory T cells but not NKT I cells are modulated by a single low-dose cyclophosphamide in a B cell lymphoma tumor-model.

AIM: Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low doses leads to an enhancement of the antitumor immune response. Our objective was to study the modulation, if any, by low dose Cy, of T regulatory (Treg) and natural killer T (NKT) I cells, two cell populations of the innate immune response with opposing effects on the tumors, in a rat B cell lymphoma model. METHODS: Inbred e rats were challenged s.c. with L-TACB lymphoma and on day 14 animals were distributed in two groups. Treated: injected i.p. with cyclophosphamide (10mg/kg of body weight) and CONTROL: injected i.p. with saline. Blood samples were taken from days 0 to 21 and the percentage of T regulatory and natural killer T I cells were determined by flow cytometry. RESULTS: We found that the increase of natural and inducible T regulatory cells of peripheral blood achieved during tumor growth was significantly downregulated by cyclophosphamide. On the contrary, natural killer T I cells were not modulated by the treatment. CONCLUSION: The antimetastatic effect of a single low dose of Cy would be due, at least in part, to downregulation of natural and inducible T regulatory cells.

[Malignant lymphoma of the skin: update on diagnostics and therapy of primary cutaneous B-cell lymphoma]. / Maligne Lymphome der Haut : Update zu Diagnostik und Therapie primär kutaner B-Zell-Lymphome.

The diagnosis of primary cutaneous B-cell lymphoma is made based principally on the results of histological investigations and staging. For an exact staging abdominal sonography and chest X-ray examinations and for appropriate clinical symptoms special investigations as well as radiological imaging procedures including PET are indicated in addition to conventional laboratory investigations. For therapy rituximab is normally administered as monotherapy in order to avoid over therapy of indolent lymphoma. Further options are radiotherapy and new approaches with electrochemotherapy as well as pegylated doxorubicin.

Cisplatin, gemcitabine, and treosulfan in relapsed stage IV cutaneous malignant melanoma patients.

To evaluate the efficacy of cisplatin, gemcitabine, and treosulfan (CGT) in 91 patients with pretreated relapsed AJCC stage IV cutaneous malignant melanoma. Patients in relapse after first-, second-, or third-line therapy received 40 mg m(-2) intravenous (i.v.) cisplatin, 1000 mg m(-2) i.v. gemcitabine, and 2500 mg m(-2) i.v. treosulfan on days 1 and 8. Cisplatin, gemcitabine, and treosulfan therapy was repeated every 5 weeks until progression of disease occurred. A maximum of 11 CGT cycles (mean, two cycles) was administered per patient. Four patients (4%) showed a partial response; 15 (17%) patients had stable disease; and 72 (79%) patients progressed upon first re-evaluation. Overall survival of all 91 patients was 6 months (2-year survival rate, 7%). Patients with partial remission or stable disease exhibited a median overall survival of 11 months (2-year survival rate, 36%), while patients with disease progression upon first re-evaluation had a median overall survival of 5 months (2-year survival rate, 0%). Treatment with CGT was efficient in one-fifth of the pretreated relapsed stage IV melanoma patients achieving disease stabilisation or partial remission with prolonged but limited survival.

Mechanotransduction in striated muscle via focal adhesion kinase.

Contractile tissues demonstrate a pronounced capacity to remodel their composition in response to mechanical challenges. Descriptive evidence suggests the upstream involvement of the phosphotransfer enzyme FAK (focal adhesion kinase) in the molecular control of load-dependent muscle plasticity. Thereby FAK evolves as a myocellular transducer of mechanical signals towards downstream transcript expression in myofibres. Recent advances in somatic gene therapy now allow the exploration of the functional involvement of this enzyme in mechanotransduction in intact muscle.

Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects.

OBJECTIVE: Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. MATERIALS: Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. METHODS: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. RESULTS: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. CONCLUSIONS: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.

Acetyl-L-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis.

The expressional profile of mitochondrial transcripts and of genes involved in the mitochondrial biogenesis pathway induced by ALCAR daily supplementation in soleus muscle of control and unloaded 3-month-old rats has been analyzed. It has been found that ALCAR treatment is able to upregulate the expression level of mitochondrial transcripts (COX I, ATP6, ND6, 16 S rRNA) in both control and unloaded animals. Interestingly, ALCAR feeding to unloaded rats resulted in the increase of transcript level for master factors involved in mitochondrial biogenesis (PGC-1alpha, NRF-1, TFAM). It also prevented the unloading-induced downregulation of mRNA levels for kinases able to transduce metabolic (AMPK) and neuronal stimuli (CaMKIIbeta) into mitochondrial biogenesis. No significant effect on the expressional level of such genes was found in control ALCAR-treated rats. In addition, ALCAR feeding was able to prevent the loss of mitochondrial protein content due to unloading condition. Correlation analysis revealed a strong coordination in the expression of genes involved in mitochondrial biogenesis only in ALCAR-treated suspended animals, supporting a differentiated effect of ALCAR treatment in relation to the loading state of the soleus muscle. In conclusions, we demonstrated the ability of ALCAR supplementation to promote only in soleus muscle of hindlimb suspended rats an orchestrated expression of genes involved in mitochondrial biogenesis, which might counteract the unloading-induced metabolic changes, preventing the loss of mitochondrial proteins.

Gene expression in skeletal muscle of coronary artery disease patients after concentric and eccentric endurance training.

Low-intensity concentric (CET) and eccentric (EET) endurance-type training induce specific structural adaptations in skeletal muscle. We evaluated to which extent steady-state adaptations in transcript levels are involved in the compensatory alterations of muscle mitochondria and myofibrils with CET versus EET at a matched metabolic exercise intensity of medicated, stable coronary patients (CAD). Biopsies were obtained from vastus lateralis muscle before and after 8 weeks of CET (n=6) or EET (n=6). Transcript levels for factors involved in mitochondrial biogenesis (PGC-1alpha, Tfam), mitochondrial function (COX-1, COX-4), control of contractile phenotype (MyHC I, IIa, IIx) as well as mechanical stress marker (IGF-I) were quantified using an reverse-transcriptase polymerase chain reaction approach. After 8 weeks of EET, a reduction of the COX-4 mRNA level by 41% and a tendency for a drop in Tfam transcript concentration (-33%, P=0.06) was noted. This down-regulation corresponded to a drop in total mitochondrial volume density. MyHC-IIa transcript levels were specifically decreased after EET, and MyHC-I mRNA showed a trend towards a reduction (P=0.08). Total fiber cross-sectional area was not altered. After CET and EET, the IGF-I mRNA level was significantly increased. The PGC-1alpha significantly correlated with Tfam, and both PGC-1alpha and Tfam significantly correlated with COX-1 and COX-4 mRNAs. Post-hoc analysis identified significant interactions between the concurrent medication and muscular transcript levels as well as fiber size. Our findings support the concept that specific transcriptional adaptations mediate the divergent mitochondrial response of muscle cells to endurance training under different load condition and indicate a mismatch of processes related to muscle hypertrophy in medicated CAD patients.

Regulatory gene expression in skeletal muscle of highly endurance-trained humans.

AIM AND BACKGROUND: Changes in regulatory and structural gene expression provide the molecular basis for the adaptation of human skeletal muscle to endurance exercise. HYPOTHESIS: The steady-state levels of multiple mRNAs mainly involved in regulatory functions differ between highly endurance-trained and untrained subjects in a muscle heavily recruited during the exercise. METHODS: Biopsies from musculus vastus lateralis of seven untrained (UT) subjects [maximal oxygen consumption (VO2max) = 39 mL kg-1 min-1] and seven trained (T) professional cyclists (VO2max = 72 mL kg-1 min-1) were analysed for the contents of 597 different mRNAs using commercially available cDNA arrays (Clontech no. 7740-1). Intra-individual expression profiles were compared by least-square linear regression analysis. Differences in gene expression between the two groups were tested for statistical significance using L1 regression analysis combined with the sign test on all permutations of scatter plots of log raw values from UT vs. T subjects. RESULTS: Transcripts for 144 of 597 genes were sufficiently abundant to be analysed quantitatively. The expression profiles of the T group had a better intragroup correlation (R2) than those of the UT group (0.78 vs. 0.65, P < 0.05). An intergroup (T vs. UT) correlation of expression profiles gave an R2 of 0.71. Statistical analysis at a false discovery rate of 5% identified differential expression of nine cell-regulatory genes between T and UT. The mRNA levels of eight genes, including two DNA repair enzymes, transcription factors, signal transducers, a glycolytic enzyme and a factor involved in steroid hormone metabolism were increased in T vs. UT. Conversely, the mRNA of the tumour suppressor APC was downregulated with endurance training. Selective reverse-transcriptase polymerase chain reaction experiments confirmed the signal estimates from the array analysis. CONCLUSIONS: The repetitive impact of the complex exercise stimuli in professional cyclists attenuated the interindividual differences in regulatory gene expression in skeletal muscle. Long-term nuclear reprogramming of regulatory gene expression seems to be characteristic of human musculus vastus lateralis in a highly endurance-trained steady state.