Cancer cachexia is characterized by the progressive loss of skeletal muscle mass. While mouse skeletal muscle's response to an acute bout of stimulated low-frequency concentric muscle contractions is disrupted by cachexia, gaps remain in our understanding of cachexia's effects on eccentric contraction-induced muscle growth. The purpose of this study was to determine whether repeated bouts of stimulated high-frequency eccentric muscle contractions [high-frequency electrical muscle stimulation (HFES)] could stimulate myofiber growth during cancer cachexia progression, and whether this training disrupted muscle signaling associated with wasting. Male Apc(Min/+) mice initiating cachexia (N = 9) performed seven bouts of HFES-induced eccentric contractions of the left tibialis anterior muscle over 2 wk. The right tibialis anterior served as the control, and mice were killed 48 h after the last stimulation. Age-matched C57BL/6 mice (N = 9) served as wild-type controls. Apc(Min/+) mice lost body weight, muscle mass, and type IIA, IIX, and IIB myofiber cross-sectional area. HFES increased myofiber cross-sectional area of all fiber types, regardless of cachexia. Cachexia increased muscle noncontractile tissue, which was attenuated by HFES. Cachexia decreased the percentage of high succinate dehydrogenase activity myofibers, which was increased by HFES, regardless of cachexia. While cachexia activated AMP kinase, STAT3, and ERK1/2 signaling, HFES decreased AMP kinase phosphorylation, independent of the suppression of STAT3. These results demonstrate that cachectic skeletal muscle can initiate a growth response to repeated eccentric muscle contractions, despite the presence of a systemic cachectic environment.

Key pointsr Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity.r Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise.r We show that the human response to exercise includes an altered expression of thousands of protein-coding genes, and much of this response appears to be driven by histamine.r Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training.Abstract Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors. In humans, aerobic exercise is followed by a post-exercise activation of histamine H 1 and H 2 receptors localized to the previously exercised muscle. This could trigger a broad range of cellular adaptations in response to exercise. Thus, we exploited RNA sequencing to explore the effects of H 1 and H 2 receptor blockade on the exercise transcriptome in human skeletal muscle tissue harvested from the vastus lateralis. We found that exercise exerts a profound influence on the human transcriptome, causing the differential expression of more than 3000 protein-coding genes. The influence of histamine blockade post-exercise was notable for 795 genes that were differentially expressed between the control and blockade condition, which represents >25% of the number responding to exercise. The broad histamine footprint on the human exercise transcriptome crosses many cellular functions, including inflammation, vascular function, metabolism, and cellular maintenance.

Histamine contributes to elevations in skeletal muscle blood flow following exercise, which raises the possibility that histamine is an important mediator of the inflammatory response to exercise. We examined the influence of antihistamines on postexercise blood flow, inflammation, muscle damage, and delayed-onset muscle soreness (DOMS) in a model of moderate exercise-induced muscle damage. Subjects consumed either a combination of fexofenadine and ranitidine (blockade, = 12) or nothing (control, = 12) before 45 min of downhill running (-10% grade). Blood flow to the leg was measured before and throughout 120 min of exercise recovery. Markers of inflammation, muscle damage, and DOMS were obtained before and at 0, 6, 12, 24, 48, and 72 h postexercise. At 60 min postexercise, blood flow was reduced ~29% with blockade compared with control ( < 0.05). Markers of inflammation were elevated after exercise (TNF-ɑ, IL-6), but did not differ between control and blockade. Creatine kinase concentrations peaked 12 h after exercise, and the overall response was greater with blockade (18.3 ± 3.2 kU·l·h) compared with control (11.6 ± 2.0 kU·l·h; < 0.05). Reductions in muscle strength in control (-19.3 ± 4.3% at 24 h) were greater than blockade (-7.8 ± 4.8%; < 0.05) and corresponded with greater perceptions of pain/discomfort in control compared with blockade. In conclusion, histamine-receptor blockade reduced postexercise blood flow, had no effect on the pattern of inflammatory markers, increased serum creatine kinase concentrations, attenuated muscle strength loss, and reduced pain perception following muscle-damaging exercise. Histamine appears to be intimately involved with skeletal muscle during and following exercise. Blocking histamine's actions during muscle-damaging exercise, via common over-the-counter antihistamines, resulted in increased serum creatine kinase, an indirect marker of muscle damage. Paradoxically, blocking histamine's actions attenuated muscle strength loss and reduced perceptions of muscle pain for 72 h following muscle-damaging exercise. These results indicate that exercise-induced histamine release may have a broad impact on protecting muscle from exercise-induced damage.

Mitochondrial myopathy with lactic acidosis and sideroblastic anemia (MLASA) is an oxidative phosphorylation disorder, with primary clinical manifestations of myopathic exercise intolerance and a macrocytic sideroblastic anemia. One cause of MLASA is recessive mutations in PUS1, which encodes pseudouridine (Ψ) synthase 1 (Pus1p). Here we describe a mouse model of MLASA due to mutations in PUS1. As expected, certain Ψ modifications were missing in cytoplasmic and mitochondrial tRNAs from Pus1−/− animals. Pus1−/− mice were born at the expected Mendelian frequency and were non-dysmorphic. At 14 weeks the mutants displayed reduced exercise capacity. Examination of tibialis anterior (TA) muscle morphology and histochemistry demonstrated an increase in the cross sectional area and proportion of myosin heavy chain (MHC) IIB and low succinate dehydrogenase (SDH) expressing myofibers, without a change in the size of MHC IIA positive or high SDH myofibers. Cytochrome c oxidase activity was significantly reduced in extracts from red gastrocnemius muscle from Pus1−/− mice. Transmission electron microscopy on red gastrocnemius muscle demonstrated that Pus1−/− mice also had lower intermyofibrillar mitochondrial density and smaller mitochondria. Collectively, these results suggest that alterations in muscle metabolism related to mitochondrial content and oxidative capacity may account for the reduced exercise capacity in Pus1−/− mice.

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Histamine‐receptor antagonists (“antihistamines”) are widely used among endurance athletes and are not currently banned by the World Anti‐Doping Agency. Our lab has recently shown that a single dose of antihistamines prior to muscle‐damaging exercise attenuates strength loss and muscle pain in the 72 hours following exercise. Histamine, produced within muscle, may be a factor in exercise‐induced muscle pain/discomfort and, therefore, perception of effort, as group III/IV muscle afferents (nociceptive neurons) are sensitized via activation of H1 and H2 receptors. Histamine may have more influence on muscle pain and effort sensations during long‐duration exercise than short‐duration, because the activity of histidine decarboxylase (the enzyme that creates histamine) increases with exercise duration. Therefore, the purpose of this experiment was to determine if combination H1/H2 antihistamines increase endurance exercise performance. It was hypothesized that H1/H2 antihistamines would decrease the time to completion of a fixed‐distance time‐trial compared to placebo, and the effect would be greater following an endurance‐exercise bout. Eleven (3F) highly competitive cyclists (Cat 1–3) performed six 10 km time‐trials on separate days. The first two trials served as a familiarization, and repeatability was assessed by calculating a coefficient of variation (CV) between times to completion. The next 4 trials were performed in a randomized‐block order. Two were preceded by 120 min of seated rest and two by 120 min of steady‐state cycling at 50% VO2peak. Within those blocks, volunteers consumed either antihistamines (540 mg fexofenadine; a H1 receptor blocker, and 300 mg of ranitidine; a H2 blocker) or placebo 60 min prior to the start of rest/exercise. The main outcome variable was 10 km time to completion. Additionally, rating of perceived exertion (RPE), isometric quadriceps muscle strength, blood glucose, and blood lactate were measured prior to and following the time‐trials. Conventional statistics (2‐Way Repeated Measures ANOVA), effect size (ES = Cohen's dz), 95% CI, and CV from familiarization trials were used to determine the presence, strength, and meaningfulness of differences, respectively, between the trials. There was a significant reduction in performance with antihistamines compared to placebo (+10.5 ± 3.8 s, mean±SEM, drug effect p=0.002), the reduced performance tended to be exacerbated by prior exercise (p=0.057) but there was no drug by prior exercise interaction (p=0.716) (Figure 1). The day‐to‐day 10 km performance variability (CV) was 0.98%. The percent change between placebo and antihistamine was likely trivial for time‐trials following rest (mean −0.87%, 95%CI −2.02 to 0.29%) (ES=0.505) and potentially harmful following exercise (mean −1.2%, 95%CI −2.45 to 0.05%) (ES=0.646). There were no drug effects on changes (pre to post time‐trial) in isometric muscle strength (p=0.607), RPE (p=0.828), blood glucose (p=0.964) or lactate (p=0.402) between antihistamine and placebo conditions. Thus, contrary t...

Aerobic exercise induces mast cell degranulation and increases histamine formation by histidine decarboxylase, resulting in an ~150% increase in intramuscular histamine. The purpose of this study was to determine if the increase in skeletal muscle temperature associated with exercise is sufficient to explain this histamine response. Specifically, we hypothesized that local passive heating that mimics the magnitude and time-course of changes in skeletal muscle temperature observed during exercise would result in increased intramuscular histamine concentrations comparable to exercising values. Seven subjects participated in the main study in which pulsed short-wave diathermy was used to passively raise the temperature of the vastus lateralis over 60 min. Heating increased intramuscular temperature from 32.6 (95% CI 32.0 to 33.2) to 38.9 (38.7 to 39.2) oC (P < 0.05) and increased intramuscular histamine concentration from 2.14 (1.92 to 2.36) to 2.97 (2.57 to 3.36) ng/ml (P < 0.05), an increase of 41%. In a follow-up in vitro experiment utilizing human-derived cultured mast cells, heating to comparable temperatures did not activate mast cell degranulation. Therefore, it appears that exercise-associated changes in skeletal muscle temperature are sufficient to generate elevations in intramuscular histamine concentration. However, this thermal effect is most likely due to changes in de novo histamine formation via histidine decarboxylase and not due to degranulation of mast cells. In conclusion, physiologically relevant increases in skeletal muscle temperature explain part, but not all, of the histamine response to aerobic exercise. This thermal effect may be important in generating the positive adaptations to exercise training.

Introduction Previous studies observed diurnal variation in hemodynamic responses during recovery from whole-body exercise, with vasodilation appearing greater after evening versus morning sessions. It is unclear what mechanism(s) underlie this response. Since small muscle-mass exercise can isolate peripheral effects related to postexercise vasodilation, it may provide insight into possible mechanisms behind this diurnal variation. Methods The study was conducted in ten healthy (5F, 5M) young individuals, following single-leg dynamic knee-extension exercise performed in the Morning (7:30–11:30 am) or the Evening (5–9 pm) on two different days, in random order. Arterial pressure (automated auscultation) and leg blood flow (femoral artery Doppler ultrasound) were measured pre-exercise and during 120 min postexercise. Net effect for each session was calculated as percent change in blood flow (or vascular conductance) between the Active Leg and the Inactive Leg. Results Following Morning exercise, blood flow was 34.9 ± 8.9% higher in the Active Leg versus the Inactive Leg ( p < 0.05) across recovery. Following Evening exercise, blood flow was 35.0 ± 8.8% higher in the Active Leg versus the Inactive Leg ( p < 0.05). Likewise, vascular conductance was higher in the Active Leg versus the Inactive Leg (Morning: +35.1 ± 9.0%, p < 0.05; Evening: +33.2 ± 8.2%, p < 0.05). Morning and Evening blood flow ( p = 0.66) and vascular conductance ( p = 0.64) did not differ. Conclusion These data suggest previous studies which identified diurnal variations in postexercise vasodilation responses are likely reflecting central rather than peripheral modulation of cardiovascular responses.