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Background: Disorders of gastric function are highly prevalent, but diagnosis often remains symptom‐based and inconclusive. Body surface gastric mapping is an emerging diagnostic solution, but current approaches lack scalability and are cumbersome and clinically impractical. We present a novel scalable system for non‐invasively mapping gastric electrophysiology in high‐resolution (HR) at the body surface. Methods: The system comprises a custom‐designed stretchable high‐resolution "peel‐and‐stick" sensor array (8 × 8 pre‐gelled Ag/AgCl electrodes at 2 cm spacing; area 225 cm2), wearable data logger with custom electronics incorporating bioamplifier chips, accelerometer and Bluetooth synchronized in real‐time to an App with cloud connectivity. Automated algorithms filter and extract HR biomarkers including propagation (phase) mapping. The system was tested in a cohort of 24 healthy subjects to define reliability and characterize features of normal gastric activity (30 m fasting, standardized meal, and 4 h postprandial). Key Results: Gastric mapping was successfully achieved non‐invasively in all cases (16 male; 8 female; aged 20–73 years; BMI 24.2 ± 3.5). In all subjects, gastric electrophysiology and meal responses were successfully captured and quantified non‐invasively (mean frequency 2.9 ± 0.3 cycles per minute; peak amplitude at mean 60 m postprandially with return to baseline in <4 h). Spatiotemporal mapping showed regular and consistent wave activity of mean direction 182.7° ± 73 (74.7% antegrade, 7.8% retrograde, 17.5% indeterminate). Conclusions and Inferences: BSGM is a new diagnostic tool for assessing gastric function that is scalable and ready for clinical applications, offering several biomarkers that are improved or new to gastroenterology practice. [ABSTRACT FROM AUTHOR]

Background: Body surface gastric mapping (BSGM) is a new clinical tool for gastric motility diagnostics, providing high‐resolution data on gastric myoelectrical activity. Artifact contamination was a key challenge to reliable test interpretation in traditional electrogastrography. This study aimed to introduce and validate an automated artifact detection and rejection system for clinical BSGM applications. Methods: Ten patients with chronic gastric symptoms generated a variety of artifacts according to a standardized protocol (176 recordings) using a commercial BSGM system (Alimetry, New Zealand). An automated artifact detection and rejection algorithm was developed, and its performance was compared with a reference standard comprising consensus labeling by 3 analysis experts, followed by comparison with 6 clinicians (3 untrained and 3 trained in artifact detection). Inter‐rater reliability was calculated using Fleiss' kappa. Key Results: Inter‐rater reliability was 0.84 (95% CI:0.77–0.90) among experts, 0.76 (95% CI:0.68–0.83) among untrained clinicians, and 0.71 (95% CI:0.62–0.79) among trained clinicians. The sensitivity and specificity of the algorithm against experts was 96% (95% CI:91%–100%) and 95% (95% CI:90%–99%), respectively, vs 77% (95% CI:68%–85%) and 99% (95% CI:96%–100%) against untrained clinicians, and 97% (95% CI:92%–100%) and 88% (95% CI:82%–94%) against trained clinicians. Conclusions & Inferences: An automated artifact detection and rejection algorithm was developed showing >95% sensitivity and specificity vs expert markers. This algorithm overcomes an important challenge in the clinical translation of BSGM and is now being routinely implemented in patient test interpretations. [ABSTRACT FROM AUTHOR]

Neutrophils accumulate in insulin-sensitive tissues during obesity and may play a role in impairing insulin sensitivity. The major serine protease expressed by neutrophils is neutrophil elastase (NE), which is inhibited endogenously by a1-antitrypsin A (A1AT). We investigated the effect of exogenous (A1AT) treatment on diet-induced metabolic dysfunction. Male C57Bl/6j mice fed a chow or a high-fat diet (HFD) were randomized to receive intraperitoneal injections three times weekly of either Prolastin (human A1AT; 2 mg) or vehicle (PBS) for 10 wk. Prolastin treatment did not affect plasma NE concentration, body weight, glucose tolerance, or insulin sensitivity in chow-fed mice. In contrast, Prolastin treatment attenuated HFD-induced increases in plasma and white adipose tissue (WAT) NE without affecting circulatory neutrophil levels or increases in body weight. Prolastin-treated mice fed a HFD had improved insulin sensitivity, as assessed by insulin tolerance test, and this was associated with higher insulin-dependent IRS-1 (insulin receptor substrate) and AktSer473 phosphorylation, and reduced inflammation markers in WAT but not liver or muscle. In 3T3-L1 adipocytes, Prolastin reversed recombinant NE-induced impairment of insulin-stimulated glucose uptake and IRS-1 phosphorylation. Furthermore, PDGF mediated p-AktSer473 activation and glucose uptake (which is independent of IRS-1) was not affected by recombinant NE treatment. Collectively, our findings suggest that NE infiltration of WAT during metabolic overload contributes to insulin resistance by impairing insulin-induced IRS-1 signaling. [ABSTRACT FROM AUTHOR]

Key points: Loss of β‐catenin impairs in vivo and isolated muscle exercise/contraction‐stimulated glucose uptake.β‐Catenin is required for exercise‐induced skeletal muscle actin cytoskeleton remodelling.β‐Catenin675 phosphorylation during exercise may be intensity dependent. The conserved structural protein β‐catenin is an emerging regulator of vesicle trafficking in multiple tissues and supports insulin‐stimulated glucose transporter 4 (GLUT4) translocation in skeletal muscle by facilitating cortical actin remodelling. Actin remodelling may be a convergence point between insulin and exercise/contraction‐stimulated glucose uptake. Here we investigated whether β‐catenin is involved in regulating exercise/contraction‐stimulated glucose uptake. We report that the muscle‐specific deletion of β‐catenin induced in adult mice (BCAT‐mKO) impairs both exercise‐ and contraction (isolated muscle)‐induced glucose uptake without affecting running performance or canonical exercise signalling pathways. Furthermore, high intensity exercise in mice and contraction of myotubes and isolated muscles led to the phosphorylation of β‐cateninS675, and this was impaired by Rac1 inhibition. Moderate intensity exercise in control and Rac1 muscle‐specific knockout mice did not induce muscle β‐cateninS675 phosphorylation, suggesting exercise intensity‐dependent regulation of β‐cateninS675. Introduction of a non‐phosphorylatable S675A mutant of β‐catenin into myoblasts impaired GLUT4 translocation and actin remodelling stimulated by carbachol, a Rac1 and RhoA activator. Exercise‐induced increases in cross‐sectional phalloidin staining (F‐actin marker) of gastrocnemius muscle was impaired in muscle from BCAT‐mKO mice. Collectively our findings suggest that β‐catenin is required for optimal glucose transport in muscle during exercise/contraction, potentially via facilitating actin cytoskeleton remodelling. Key points: Loss of β‐catenin impairs in vivo and isolated muscle exercise/contraction‐stimulated glucose uptake.β‐Catenin is required for exercise‐induced skeletal muscle actin cytoskeleton remodelling.β‐Catenin675 phosphorylation during exercise may be intensity dependent. [ABSTRACT FROM AUTHOR]

Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1-6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease. [ABSTRACT FROM AUTHOR]

Humanin is a small regulatory peptide encoded within the 16S ribosomal RNA gene (MT-RNR2) of the mitochondrial genome that has cellular cyto- and metaboloprotective properties similar to that of aerobic exercise training. Here we investigated whether acute high-intensity interval exercise or short-term high-intensity interval training (HIIT) impacted skeletal muscle and plasma humanin levels. Vastus lateralis muscle biopsies and plasma samples were collected from young healthy untrained men (n ≡ 10, 24.5 3.7 yr) before, immediately following, and 4 h following the completion of 10 x 60 s cycle ergometer bouts at V˙O2peak power output (untrained). Resting and postexercise sampling was also performed after six HIIT sessions (trained) completed over 2 wk. Humanin protein abundance in muscle and plasma were increased following an acute high-intensity exercise bout. HIIT trended (P ≡ 0.063) to lower absolute humanin plasma levels, without effecting the response in muscle or plasma to acute exercise. A similar response in the plasma was observed for the small humanin-like peptide 6 (SHLP6), but not SHLP2, indicating selective regulation of peptides encoded by MT-RNR2 gene. There was a weak positive correlation between muscle and plasma humanin levels, and contraction of isolated mouse EDL muscle increased humanin levels ~4-fold. The increase in muscle humanin levels with acute exercise was not associated with MT-RNR2 mRNA or humanin mRNA levels (which decreased following acute exercise). Overall, these results suggest that humanin is an exercise-sensitive mitochondrial peptide and acute exercise-induced humanin responses in muscle are nontranscriptionally regulated and may partially contribute to the observed increase in plasma concentrations. NEW & NOTEWORTHY Small regulatory peptides encoded within the mitochondrial genome (mitochondrial derived peptides) have been shown to have cellular cyto- and metabolo-protective roles that parallel those of exercise. Here we provide evidence that humanin and SHLP6 are exercise-sensitive mitochondrial derived peptides. Studies to determine whether mitochondrial derived peptides play a role in regulating exercise-induced adaptations are warranted. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) regulate gene expression via transcript degradation and translational inhibition, and they may also function as long distance signaling molecules. Circulatory miRNAs are either protein-bound or packaged within vesicles (exosomes). Ten young men (24.6 ± 4.0 yr) underwent a single bout of high-intensity interval cycling exercise. Vastus lateralis biopsies and plasma were collected immediately before and after exercise, as well as 4 h following the exercise bout. Twenty-nine miRNAs previously reported to be regulated by acute exercise were assessed within muscle, venous plasma, and enriched circulatory exosomes via qRT-PCR. Of the 29 targeted miRNAs, 11 were altered in muscle, 8 in plasma, and 9 in the exosome fraction. Although changes in muscle and plasma expression were bidirectional, all regulated exosomal miRNAs increased following exercise. Three miRNAs were altered in all three sample pools (miR-1-3p, -16-5p, and -222-3p), three in both muscle and plasma (miR-21-5p, -134-3p, and -107), three in both muscle and exosomes (miR-23a-3p, -208a-3p, and -150-5p), and three in both plasma and exosomes (miR-486-5p, -126-3p, and -378a-5p). There was a marked discrepancy between the observed alterations between sample pools. A subset of exosomal miRNAs increased in abundance following exercise, suggesting an exercise-induced release of exosomes enriched in specific miRNAs. The uniqueness of the exosomal miRNA response suggests its relevance as a sample pool that needs to be further explored in better understanding biological functions. [ABSTRACT FROM AUTHOR]

One of the main sources of reactive oxygen species (ROS) in skeletal muscle is the mitochondria. Prolonged or very high ROS exposure causes oxidative damage, which can be deleterious to muscle function, and as such, there is growing interest in targeting antioxidants to the mitochondria in an effort to prevent or treat muscle dysfunction and damage associated with disease and injury. Paradoxically, however, ROS also act as important signalling molecules in controlling cellular homeostasis, and therefore caution must be taken when supplementing with antioxidants. It is possible that mitochondria-targeted antioxidants may limit oxidative stress without suppressing ROS from non-mitochondrial sources that might be important for cell signalling. Therefore, in this review, we summarise literature relating to the effect of mitochondria-targeted antioxidants on skeletal muscle function. Overall, mitochondria-targeted antioxidants appear to exert beneficial effects on mitochondrial capacity and function, insulin sensitivity and age-related declines in muscle function. However, it seems that this is dependent on the type of mitochondrial-trageted antioxidant employed, and its specific mechanism of action, rather than simply targeting to the mitochondria. [ABSTRACT FROM AUTHOR]

The article presents a study that links NOX4-derived reactive oxygen species (ROS) in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity. It mentions that reactive oxygen species (ROS) generated during exercise has been considered integral for the health-promoting effects of exercise.