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.

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, $\dot{\text{V}}$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.

The effect of an additional neurological injury (suprascapular nerve traction injury) to a chronically retracted rotator cuff muscle is incompletely understood and warrants clarification. To investigate the microscopic and macroscopic muscle degeneration patterns caused by tendon release and/or muscle denervation in a sheep rotator cuff model. Controlled laboratory study. 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. 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. 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. 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.