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Background: The training of elite skiers follows a systematic seasonal periodization with a preparation period, when anaerobic muscle strength, aerobic capacity, and cardio-metabolic recovery are specifically conditioned to provide extra capacity for developing ski-specific physical fitness in the subsequent competition period. We hypothesized that periodization-induced alterations in muscle and metabolic performance demonstrate important variability, which in part is explained by gene-associated factors in association with sex and age. Methods: A total of 34 elite skiers (20.4 ± 3.1 years, 19 women, 15 men) underwent exhaustive cardiopulmonary exercise and isokinetic strength testing before and after the preparation and subsequent competition periods of the World Cup skiing seasons 2015–2018. Biometric data were recorded, and frequent polymorphisms in five fitness genes, ACE-I/D (rs1799752), TNC (rs2104772), ACTN3 (rs1815739), and PTK2 (rs7460, rs7843014), were determined with specific PCR reactions on collected DNA. Relative percentage changes of cardio-pulmonary and skeletal muscle metabolism and performance over the two seasonal periods were calculated for 160 data points and subjected to analysis of variance (ANOVA) to identify hypothesized and novel associations between performance alterations and the five respective genotypes and determine the influence of age × sex. A threshold of 0.1 for the effect size (h2) was deemed appropriate to identify relevant associations and motivate a post hoc test to localize effects. Results: The preparation and competition periods produced antidromic functional changes, the extent of which varied with increasing importance for anaerobic strength, aerobic performance, cardio-metabolic efficiency, and cardio-metabolic/muscle recovery. Only peak RER (−14%), but not anaerobic strength and peak aerobic performance, and parameters characterizing cardio-metabolic efficiency, differed between the first and last studied skiing seasons because improvements over the preparation period were mostly lost over the competition period. A number of functional parameters demonstrated associations of variability in periodic changes with a given genotype, and this was considerably influenced by athlete “age”, but not “sex”. This concerned age-dependent associations between periodic changes in muscle-related parameters, such as anaerobic strength for low and high angular velocities of extension and flexion and blood lactate concentration, with rs1799752 and rs2104772, whose gene products relate to sarcopenia. By contrast, the variance in period-dependent changes in body mass and peak VO2 with rs1799752 and rs2104772, respectively, was independent of age. Likely, the variance in periodic changes in the reliance of aerobic performance on lactate, oxygen uptake, and heart rate was associated with rs1815739 independent of age. These associations manifested at the post hoc level in genotype-associated differences in critical performance parameters. ACTN3 T-allele carriers demonstrated, compared to non-carriers, largely different periodic changes in the muscle-associated parameters of aerobic metabolism during exhaustive exercise, including blood lactate and respiration exchange ratio. The homozygous T-allele carriers of rs2104772 demonstrated the largest changes in extension strength at low angular velocity during the preparation period. Conclusions: Physiological characteristics of performance in skiing athletes undergo training period-dependent seasonal alterations the extent of which is largest for muscle metabolism-related parameters. Genotype associations for the variability in changes of aerobic metabolism-associated power output during exhaustive exercise and anaerobic peak power over the preparation and competition period motivate personalized training regimes. This may help to predict and maximize the benefit of physical conditioning of elite skiers based on chronological characteristics and the polymorphisms of the ACTN3, ACE, and TNC genes investigated here.

Atrophy and fat accumulation are debilitating aspects of muscle diseases and are rarely prevented. Using a vertical approach combining anatomic techniques with omics methodology in a tenotomy-induced sheep model of rotator cuff disease, we tested whether mitochondrial dysfunction is implicated in muscle wasting and perturbed lipid metabolism, speculating that both can be prevented by the stimulation of β-oxidation with l-carnitine. The infraspinatus muscle lost 22% of its volume over the first 6 weeks after tenotomy before the area-percentage of lipid increased from 8% to 18% at week 16. Atrophy was associated with the down-regulation of mitochondrial transcripts and protein and a slow-to-fast shift in muscle composition. Correspondingly, amino acid levels were increased 2 weeks after tendon release, when the levels of high-energy phosphates and glycerophospholipids were lowered. l-Carnitine administration (0.9 g/kg per day) prevented atrophy over the first 2 weeks, and mitigated alterations of glutamate, glycerophospholipids, and carnitine levels in released muscle, but did not prevent the level decrease in high-energy phosphates or protein constituents of mitochondrial respiration, promoting the accumulation of longer lipids with an increasing saturation. We conclude that the early phase of infraspinatus muscle degeneration after tendon release involves the elimination of oxidative characteristics associated with an aberrant accumulation of lipid species but is largely unrelated to the prevention of atrophy with oral l-carnitine administration.

Background:Muscle atrophy and fatty infiltration are limiting factors for successful rotator cuff (RC) repair. Quantitative data regarding these hallmarks of degenerative muscle changes after RC repair in humans are scarce. By utilizing a new application of the 6-point Dixon magnetic resonance imaging technology, 3-dimensional volume and fat fraction analysis of the whole RC muscle have become possible.Purpose:Quantitative analysis of atrophy and fatty infiltration of the supraspinatus muscle after healed and failed RC tendon-to-bone repair.Study Design:Cohort study; Level of evidence, 3.Methods:Muscle volume and fat fraction were measured preoperatively and at 3 and 12 months postoperatively in 19 failed and 21 healed arthroscopic supraspinatus tendon repairs, with full muscle volume segmentation and magnetic resonance Dixon sequences.Results:In both groups, the muscle volume initially decreased 3 months after RC repair by –3% in intact ( P = .140) and –10% in failed repair ( P = .004) but recovered between 3 and 12 months to 103% ( P = .274) in intact and 92% ( P = .040) in failed repairs when compared with the preoperative volume (difference of change between groups, preoperative to 12 month: P = .013). The supraspinatus muscle’s fat fraction did not significantly change after successful repair (6.5% preoperative, 6.6% after 3 months, and 6.7% after 12 months; all nonsignificant). There was, however, a significant increase from 7.8% to 10.8% at 3 months ( P = .014) and 11.4% at 12 months ( P = .020) after failed repair (difference between groups at 3- and 12-month follow-up: P = .018 and P = .001, respectively).Conclusion:After successful arthroscopic repair, RC tendon tear–induced fatty infiltration can be almost stopped, and muscle atrophy can even be slightly reversed. In case of a failed repair, however, these changes are further pronounced during the first 3 postoperative months but seem to stabilize thereafter.

INTRODUCTION We evaluated the contribution of denervation-related molecular processes to rotator cuff muscle degeneration after tendon release. METHODS We assessed the levels of myogenic (myogenin and myogenic differentiation factor [myoD]) and pro-adipogenic (peroxisome proliferator-activated receptor gamma) transcription factors; the denervation-associated proteins tenascin-C, laminin-2, and calcium/calmodulin dependent kinase II (CaMKII); and cellular alterations in sheep after infraspinatus tenotomy (TEN), suprascapular neurectomy (NEU), or both (TEN-NEU). RESULTS Extracellular ground substance increased at the expense of contractile tissue 16 weeks after surgery, correlating with CaMKII isoform levels. Sheep undergoing NEU and TEN-NEU had exaggerated infraspinatus atrophy and increased fast fibers compared with TEN sheep. The βMCaMKII isoform levels increased with tenotomy, and myoD levels tripled after denervation and were associated with slow fibers. DISCUSSION In sheep, denervation did not affect muscle-to-fat conversion after tenotomy of the infraspinatus. Furthermore, concurrent neurectomy mitigated the loss of fast fibers after tenotomy by inducing a fast-contractile phenotype. This article is protected by copyright. All rights reserved.

Background:The effect of an additional neurological injury (suprascapular nerve traction injury) to a chronically retracted rotator cuff muscle is incompletely understood and warrants clarification.Purpose:To investigate the microscopic and macroscopic muscle degeneration patterns caused by tendon release and/or muscle denervation in a sheep rotator cuff model.Study Design:Controlled laboratory study.Methods:Infraspinatus muscle biopsy specimens (for histological analysis) were obtained from 18 Swiss alpine sheep before and 16 weeks after release of the infraspinatus tendon (tenotomy [T] group; n = 6), transection of the suprascapular nerve (neurectomy [N] group; n = 6), or tendon release plus nerve transection (tenotomy + neurectomy [T&N] group; n = 6). Magnetic resonance imaging (MRI) and computed tomography (CT) were used to assess retraction (CT), muscle density (CT), volume (MRI T2), and fat fraction (MRI Dixon). Stiffness of the infraspinatus was measured with a spring scale.Results:At 16 weeks postoperatively, the mean infraspinatus muscle volume had decreased significantly more after neurectomy (to 47% ± 7% of the original volume; P = .001) and tenotomy plus neurectomy (48% ± 13%; P = .005) than after tenotomy alone (78% ± 11%). Conversely, the mean amount of intramuscular fat (CT/MRI Dixon) was not significantly different in the 3 groups (T group: 50% ± 9%; N group: 40% ± 11%; T&N group: 46% ± 10%) after 16 weeks. The mean myotendinous retraction (CT) was not significantly different in the T and T&N groups (5.8 ± 1.0 cm and 6.4 ± 0.4 cm, respectively; P = .26). Stiffness was, however, most increased after additional neurectomy. In contrast to muscle changes after tendon release, denervation of the muscle led to a decrease in the pennation angle of lengthened muscle fibers, with a reduced mean cross-sectional area of pooled muscle fibers, a slow- to fast-type transformation, and an increase in the area percentage of hybrid fibers, leading to overall significantly greater atrophy of the corresponding muscle.Conclusion:Although it is unclear which experimental group (T or T&N) most accurately reflects the clinical scenario in a given case, these findings provide baseline information for clinical differentiation between muscle changes caused by denervation or rotator cuff tendon lesions.Clinical Relevance:The findings of this study help to understand how and to which extent a neurological lesion of the supplying suprascapular nerve could influence the pattern of anatomic-physiological muscular changes after rotator cuff tendon tears.

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.

Introduction Gene polymorphisms are associated with athletic phenotypes relying on maximal or continued power production and affect the specialization of skeletal muscle composition with endurance or strength training of untrained subjects. We tested whether prominent polymorphisms in genes for angiotensin converting enzyme (ACE), tenascin-C (TNC), and actinin-3 (ACTN3) are associated with the differentiation of cellular hallmarks of muscle metabolism and contraction in high level athletes. Methods Muscle biopsies were collected from m. vastus lateralis of three distinct phenotypes; endurance athletes (n = 29), power athletes (n = 17), and untrained non-athletes (n = 63). Metabolism-, and contraction-related cellular parameters (such as capillary-to-fiber ratio, capillary length density, volume densities of mitochondria and intramyocellular lipid, fiber mean cross sectional area (MCSA) and volume densities of myofibrils) and the volume densities of sarcoplasma were analyzed by quantitative electron microscopy of the biopsies. Gene polymorphisms of ACE (I/D (insertion/deletion), rs1799752), TNC (A/T, rs2104772), and ACTN3 (C/T, rs1815739) were determined using high-resolution melting polymerase chain reaction (HRM-PCR). Genotype distribution was assessed using Chi$^{2}$ tests. Genotype and phenotype effects were analyzed by univariate or multivariate analysis of variance and post hoc test of Fisher. P-values below 0.05 were considered statistically significant. Results The athletes demonstrated the specialization of metabolism- and contraction-related cellular parameters. Differences in cellular parameters could be identified for genotypes rs1799752 and rs2104772, and localized post hoc when taking the interaction with the phenotype into account. Between endurance and power athletes these concerned effects on capillary length density for rs1799752 and rs2104772, fiber type distribution and volume densities of myofibrils (rs1799752), and MSCA (rs2104772). Endurance athletes carrying the I-allele of rs1799752 demonstrated 50%-higher volume densities of mitochondria and sarcoplasma, when power athletes that carried only the D-allele showed the highest fiber MCSAs and a lower percentage of slow type muscle fibers. Discussion ACE and tenascin-C gene polymorphisms are associated with differences in cellular aspects of muscle metabolism and contraction in specifically-trained high level athletes. Quantitative differences in muscle fiber type distribution and composition, and capillarization in knee extensor muscle explain, in part, identified associations of the insertion/deletion genotypes of ACE (rs1799752) with endurance- and power-type Sports.

We evaluated the contribution of denervation-related molecular processes to rotator cuff muscle degeneration after tendon release.We assessed the levels of myogenic (myogenin and myogenic differentiation factor [myoD]) and proadipogenic (peroxisome proliferator-activated receptor γ) transcription factors; the denervation-associated proteins tenascin-C, laminin-2, and calcium/calmodulin-dependent kinase II (CaMKII); and cellular alterations in sheep after infraspinatus tenotomy (TEN), suprascapular neurectomy (NEU), or both (TEN-NEU).Extracellular ground substance increased at the expense of contractile tissue 16 weeks after surgery, correlating with CaMKII isoform levels. Sheep undergoing NEU and TEN-NEU had exaggerated infraspinatus atrophy and increased fast fibers compared with TEN sheep. The βMCaMKII isoform levels increased with TEN, and myoD levels tripled after denervation and were associated with slow fibers.In sheep, denervation did not affect muscle-to-fat conversion after TEN of the infraspinatus. Furthermore, concurrent NEU mitigated the loss of fast fibers after TEN by inducing a fast-contractile phenotype. Muscle Nerve 59:100-107, 2019.

The insertion/deletion polymorphism in the gene for the regulator of vascular tone, angiotensin-converting enzyme (ACE), is the prototype of a genetic influence on physical fitness and this involves an influence on capillary supply lines and dependent aerobic metabolism in skeletal muscle. The respective interaction of ACE-I/D genotype and training status on local metabolic and angiogenic reactions in exercised muscle is not known. Toward this end we characterized the metabolomic and angiogenic response in knee extensor muscle, m. vastus lateralis, in 18 untrained and 34 endurance-trained (physically active, V˙O2max > 50 mL min−1 kg−1) white British men to an exhaustive bout of one-legged cycling exercise. We hypothesized that training status and ACE-I/D genotype affect supply-related muscle characteristics of exercise performance in correspondence to ACE expression and angiotensin 2 levels. ACE-I/D genotype and training status developed an interaction effect on the cross-sectional area (CSA) of m. vastus lateralis and mean CSA of slow type fibers, which correlated with peak power output (r ≥ 0.44). Genotype × training interactions in muscle also resolved for exercise-induced alterations of 22 metabolites, 8 lipids, glycogen concentration (p = 0.016), ACE transcript levels (p = 0.037), and by trend for the pro-angiogenic factor tenascin-C post exercise (p = 0.064). Capillary density (p = 0.001), capillary-to-fiber ratio (p = 0.010), systolic blood pressure (p = 0.014), and exercise-induced alterations in the pro-angiogenic protein VEGF (p = 0.043) depended on the ACE-I/D genotype alone. Our observations indicate that variability in aerobic performance in the studied subjects was in part reflected by an ACE-I/D-genotype-modulated metabolic phenotype of a major locomotor muscle. Repeated endurance exercise appeared to override this genetic influence in skeletal muscle by altering the ACE-related metabolic response and molecular aspects of the angiogenic response to endurance exercise., Frontiers in Physiology, 8, ISSN:1664-042X

Inter-individual 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 to 72.1 ml.min(-1) .kg(-1) ) no factor related to skeletal muscle structure (% slow twitch fibre content, number of capillaries per fibre), 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 (R(2) = 0.94; P < 0.001), but was lower for cycling EE (R(2) = 0.23; P < 0.023). 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, e.g., 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.

AIMS We assessed focal adhesion kinase (FAK) response to concentric (CON) versus eccentric (ECC) resistance training (RT) at two vastus lateralis (VL) sites, and the relationships between FAK, muscle protein synthesis (MPS), and morphological remodeling. 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 midbelly (MID) and distal (Distal) sites at 0, 4, 8 weeks. FAK 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

Background Medulloblastomas are malignant childhood brain tumors that arise due to the aberrant activity of developmental pathways during postnatal cerebellar development and in adult humans. Transcriptome analysis has identified four major medulloblastoma subgroups. One of them, the Sonic hedgehog (SHH) subgroup, is caused by aberrant Hedgehog signal transduction due to mutations in the Patched1 (PTCH1) receptor or downstream effectors. Mice carrying a Patched-1 null allele (Ptch1 ∆/+) are a good model to study the alterations underlying medulloblastoma development as a consequence of aberrant Hedgehog pathway activity. Results Transcriptome analysis of human medulloblastomas shows that SERPINE2, also called Protease Nexin-1 (PN-1) is overexpressed in most medulloblastomas, in particular in the SHH and WNT subgroups. As siRNA-mediated lowering of SERPINE2/PN-1 in human medulloblastoma DAOY cells reduces cell proliferation, we analyzed its potential involvement in medulloblastoma development using the Ptch1 ∆/+ mouse model. In Ptch1 ∆/+ mice, medulloblastomas arise as a consequence of aberrant Hedgehog pathway activity. Genetic reduction of Serpine2/Pn-1 interferes with medulloblastoma development in Ptch1 ∆/+ mice, as ~60% of the pre-neoplastic lesions (PNLs) fail to develop into medulloblastomas and remain as small cerebellar nodules. In particular the transcription factor Atoh1, whose expression is essential for development of SHH subgroup medulloblastomas is lost. Comparative molecular analysis reveals the distinct nature of the PNLs in young Ptch1 ∆/+ Pn-1 Δ/+ mice. The remaining wild-type Ptch1 allele escapes transcriptional silencing in most cases and the aberrant Hedgehog pathway activity is normalized. Furthermore, cell proliferation and the expression of the cell-cycle regulators Mycn and Cdk6 are significantly reduced in PNLs of Ptch1 ∆/+ Pn-1 Δ/+ mice. Conclusions Our analysis provides genetic evidence that aberrant Serpine2/Pn-1 is required for proliferation of human and mouse medulloblastoma cells. In summary, our analysis shows that Serpine2/PN-1 boosts malignant progression of PNLs to medulloblastomas, in which the Hedgehog pathway is activated in a SHH ligand-independent manner.

Angiotensin 2 is a major vasoconstrictor and subject to complex regulation. It is produced by the angiotensinconverting enzyme (ACE), which is itself regulated by blood flow and represents a target for pharmacological (lisinopril) and genetical (ACE-I/D polymorphism) influences. 32 healthy Caucasian men of British descent, including six subjects that were treated with lisinopril, completed standardized one-legged cycling-type endurance exercise to assess ACE-I/D and lisinopril dependent levels alterations of ACE and hypoxia-modulated transcripts in knee extensor muscle. Lisinopril treatment revealed significantly decreased transcript expression at baseline (COX4I1-88%; COX4I2 -67%; HIF-1α -93%) and 3 hours into recovery (HIF-1α -78%; ACE -62%). Furthermore, during recovery from cycling-type endurance exercise, COX4I2 mRNA expression was increased by 281% in ACE-II genotypes (p

Background: The multi-meric calcium/calmodulin-dependent protein kinase II (CaMKII) is the main CaMK in skeletal muscle and its expression increases with endurance training. CaMK family members are implicated in contraction-induced regulation of calcium handling, fast myosin type IIA expression and mitochondrial biogenesis. The objective of this study was to investigate the role of an increased CaMKII content for the expression of the contractile and mitochondrial phenotype in vivo. Towards this end we attempted to co-express alpha-and beta-CaMKII isoforms in skeletal muscle and characterised the effect on the contractile and mitochondrial phenotype. Results: Fast-twitch muscle m. gastrocnemius (GM) and slow-twitch muscle m. soleus (SOL) of the right leg of 3-month old rats were transfected via electro-transfer of injected expression plasmids for native α/β CaMKII. Effects were identified from the comparison to control-transfected muscles of the contralateral leg and non-transfected muscles. α/β CaMKII content in muscle fibres was 4-5-fold increased 7 days after transfection. The transfection rate was more pronounced in SOL than GM muscle (i.e. 12.6 vs. 3.5%). The overexpressed α/β CaMKII was functional as shown through increased threonine 287 phosphorylation of ß-CaMKII after isometric exercise and down-regulated transcripts COXI, COXIV, SDHB after high-intensity exercise in situ. α/β CaMKII overexpression under normal cage activity accelerated excitation-contraction coupling and relaxation in SOL muscle in association with increased SERCA2, ANXV and fast myosin type IIA/X content but did not affect mitochondrial protein content. These effects were observed on a background of regenerating muscle fibres. Conclusion: Elevated CaMKII content promotes a slow-to-fast type fibre shift in regenerating muscle but is not sufficient to stimulate mitochondrial biogenesis in the absence of an endurance stimulus.

We hypothesised that load-sensitive expression of costameric proteins, which hold the sarcomere in place and position the mitochondria, contributes to the early adaptations of antigravity muscle to unloading and would depend on muscle fibre composition and chymotrypsin activity of the proteasome. Biopsies were obtained from vastus lateralis (VL) and soleus (SOL) muscles of eight men before and after 3 days of unilateral lower limb suspension (ULLS) and subjected to fibre typing and measures for costameric (FAK and FRNK), mitochondrial (NDUFA9, SDHA, UQCRC1, UCP3, and ATP5A1), and MHCI protein and RNA content. Mean cross-sectional area (MCSA) of types I and II muscle fibres in VL and type I fibres in SOL demonstrated a trend for a reduction after ULLS (0.05≤P<0.10). FAK phosphorylation at tyrosine 397 showed a 20% reduction in VL muscle (P=0.029). SOL muscle demonstrated a specific reduction in UCP3 content (-23%;P = 0.012). Muscle-specific effects of ULLS were identified for linear relationships between measured proteins, chymotrypsin activity and fibre MCSA. The molecular modifications in costamere turnover and energy homoeostasis identify that aspects of atrophy and fibre transformation are detectable at the protein level in weight-bearing muscles within 3 days of unloading.

PURPOSE We explored whether altered expression of factors tuning mitochondrial metabolism contributes to muscular adaptations with endurance training in the condition of lowered ambient oxygen concentration (hypoxia) and whether these adaptations relate to oxygen transfer as reflected by subsarcolemmal mitochondria and oxygen metabolism in muscle. METHODS Male volunteers completed 30 bicycle exercise sessions in normoxia or normobaric hypoxia (4,000 m above sea level) at 65% of the respective peak aerobic power output. Myoglobin content, basal oxygen consumption, and re-oxygenation rates upon reperfusion after 8 min of arterial occlusion were measured in vastus muscles by magnetic resonance spectroscopy. Biopsies from vastus lateralis muscle, collected pre and post a single exercise bout, and training, were assessed for levels of transcripts and proteins being associated with mitochondrial metabolism. RESULTS Hypoxia specifically lowered the training-induced expression of markers of respiratory complex II and IV (i.e. SDHA and isoform 1 of COX-4; COX4I1) and preserved fibre cross-sectional area. Concomitantly, trends (p < 0.10) were found for a hypoxia-specific reduction in the basal oxygen consumption rate, and improvements in oxygen repletion, and aerobic performance in hypoxia. Repeated exercise in hypoxia promoted the biogenesis of subsarcolemmal mitochondria and this was co-related to expression of isoform 2 of COX-4 with higher oxygen affinity after single exercise, de-oxygenation time and myoglobin content (r ≥ 0.75). Conversely, expression in COX4I1 with training correlated negatively with changes of subsarcolemmal mitochondria (r < -0.82). CONCLUSION Hypoxia-modulated adjustments of aerobic performance with repeated muscle work are reflected by expressional adaptations within the respiratory chain and modified muscle oxygen metabolism.

High prevalence of human herpesvirus type 8 (HHV-8) infection has been reported on the island of Sardinia. Among emigrants from Sardinia, rates of HHV-8 infection are lower than they are in Sardinia and are similar to those observed in the local population. Thus, environmental factors seem to play a relevant role in affecting the prevalence of HHV-8 infection.