Exposome on skeletal muscle system: a mini-review.

Exposomics is an ever-expanding field which captures the cumulative exposures to chemical, biological, physical, lifestyle, and social factors associated with biological responses. Since skeletal muscle is currently considered as the largest secretory organ and shows substantial plasticity over the life course, this reviews addresses the topic of exposome and skeletal muscle by reviewing the state-of-the-art evidence and the most intriguing perspectives. Muscle stem cells react to stressors via phosphorylated eukaryotic initiation factor 2α and tuberous sclerosis 1, and are sensible to hormetic factors via sirtuin 1. Microplastics can delay muscle regeneration via p38 mitogen-activated protein kinases and induce transdifferentiation to adipocytes via nuclear factor kappa B. Acrolein can inhibit myogenic differentiation and disrupt redox system. Heavy metals have been associated with reduced muscle strength in children. The deep study of pollutants and biological features can shed new light on neuromuscular pathophysiology. The analysis of a time-varying and dynamic exposome risk score from a panel of exposure and phenotypes of interest is promising. The systematization of hormetic factors and the role of the microbiota in modulating the effects of exposure on skeletal muscle responses are also promising. The comprehensive exposure assessment and its interactions with endogenous processes and the resulting biological effects deserve more efforts in the field of muscle health across the lifespan.

Extracellular Vesicles in Environmental Toxicological Studies: Association between Urinary Concentrations of Phthalate Metabolites and Exosomal miRNA Expression Profiles.

Phthalates are chemical compounds, mainly used as additives in plastics, which are known to induce harmful impacts to the environment and human health due to their ability to act as hormone-mimics. Few studies have been reported on the relationship between human exposure to phthalates and the level of circulating microRNAs (miRs), especially those miRs encapsulated in extracellular vesicles/exosomes or exosome-like vesicles (ELVs). We examined the relationship of ELV-miR expression patterns and urine of adult men with five phthalate metabolites (i.e., mono isobutyl phthalate, mono-n-butyl phthalate, mono benzyl phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethylhexyl) phthalate) to identify potential biomarkers and relevant pathways. We found significant positive associations which were further confirmed by multivariable analysis. Overall, our analyses showed that the Σ phthalate metabolite concentration was associated with a significant increase in the expression level of two miRs found in ELV: miR-202 and miR-543. Different pathways including cancer and immune-related responses were predicted to be involved in this relationship. Analyzing the specific downstream target genes of miR-202 and miR-543, we identified the phosphatase and tensin homolog (PTEN) as the key gene in several converging pathways. In summary, the obtained results demonstrate that exposure to environmental phthalates could be related to altered expression profiles of specific ELV-miRs in adult men, thereby demonstrating the potential of miRs carried by exosomes to act as early effect biomarkers.

Myalgic encephalomyelitis/chronic fatigue syndrome from current evidence to new diagnostic perspectives through skeletal muscle and metabolic disturbances.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a demanding medical condition for patients and society. It has raised much more public awareness after the COVID-19 pandemic since ME/CFS and long-COVID patients share many clinical symptoms such as debilitating chronic fatigue. However, unlike long COVID, the etiopathology of ME/CFS remains a mystery despite several decades' research. This review moves from pathophysiology of ME/CFS through the compelling evidence and most interesting hypotheses. It focuses on the pathophysiology of skeletal muscle by proposing the hypothesis that skeletal muscle tissue offers novel opportunities for diagnosis and treatment of this syndrome and that new evidence can help resolve the long-standing debate on terminology.

Nutritional physiology and body composition changes during a rapid ascent to high altitude.

Exposure to high altitude might cause the body to adapt with negative energy and fluid balance that compromise body composition and physical performance. In this field study involving 12 healthy adults, sex-balanced, and aged 29 ± 4 years with a body mass index of 21.6 ± 1.8 kg/m2, we investigated the effects of a 4-day trekking up to 4556 m a.s.l. on Monte Rosa (Alps, Italy). The food intake was recorded using food diaries and nutrient averages were calculated. The bio-impedance analysis was performed at low and high altitudes, and a wearable biosensor (Swemax) was used to track hydro-saline losses in two participants. Daily total energy intake was 3348 ± 386 kcal for males and 2804 ± 415 kcal for females (13%-14% protein, 35% fat, 44%-46% carbohydrates). Although there was a significant body weight loss (65.0 ± 9.3 vs. 64.2 ± 9.10 kg, p < 0.001, d = 1.398), no significant changes in body composition parameter were found but a trend in the increase of the bioelectrical phase angle in males (p = 0.059, d = -0.991). Body water percentage significantly changed (p = 0.026, η2 p = 0.440), but the absolute water did not, suggesting that the weight loss was not due to water loss. Salivary and urinary osmolality did not change. A reduction in sweat rate at higher altitudes was observed in both participants. Interestingly, salivary leptin increased (p = 0.014, η2 p = 0.510), and salivary ghrelin decreased (p = 0.036, η2 p  = 0.403). Therefore, the 4-day trekking at altitude of hypoxia exposure induced changes in satiety and appetite hormones. High altitude expeditions require more specific nutritional guidance, and using multiplex analysis could help in monitoring fluid balance and body composition.

Oral bacteriome and oral potentially malignant disorders: A systematic review of the associations.

INTRODUCTION: Periodontal bacteria can infiltrate the epithelium, activate signaling pathways, induce inflammation, and block natural killer and cytotoxic cells, all of which contribute to the vicious circle of carcinogenesis. It is unknown whether oral dysbiosis has an impact on the etiology or prognosis of OPMD. AIMS: Within this paradigm, this work systemically investigated and reported on the composition of oral microbiota in patients with oral potentially malignant disorders (OPMD) versus healthy controls. METHODS: Observational studies that reported next generation sequencing analysis of oral tissue or salivary samples and found at least three bacterial species were included. Identification, screening, citation analysis, and graphical synthesis were carried out. RESULTS: For oral lichen planus (OLP), the bacteria with the highest abundance were Fusobacterium, Capnocytophaga, Gemella, Granulicatella, Porphyromonas, and Rothia; for oral leukoplakia (OLK), Prevotella. Streptococci levels in OLK and OLP were lower. The usage of alcohol or smoke had no effect on the outcomes. CONCLUSIONS: An increase in periodontal pathogenic bacteria could promote the development and exacerbation of lichen. Effective bacteriome-based biomarkers are worthy of further investigation and application, as are bacteriome-based treatments.

Integrated procedures for accelerating, deepening, and leading genetic inquiry: A first application on human muscle secretome.

PURPOSE: Beyond classical procedures, bioinformatic-assisted approaches and computational biology offer unprecedented opportunities for scholars. However, these amazing possibilities still need epistemological criticism, as well as standardized procedures. Especially those topics with a huge body of data may benefit from data science (DS)-assisted methods. Therefore, the current study dealt with the combined expert-assisted and DS-assisted approaches to address the broad field of muscle secretome. We aimed to apply DS tools to fix the literature research, suggest investigation targets with a data-driven approach, predict possible scenarios, and define a workflow. METHODS: Recognized scholars with expertise on myokines were invited to provide a list of the most important myokines. GeneRecommender, GeneMANIA, HumanNet, and STRING were selected as DS tools. Networks were built on STRING and GeneMANIA. The outcomes of DS tools included the top 5 recommendations. Each expert-led discussion has been then integrated with an DS-led approach to provide further perspectives. RESULTS: Among the results, 11 molecules had already been described as bona-fide myokines in literature, and 11 molecules were putative myokines. Most of the myokines and the putative myokines recommended by the DS tools were described as present in the cargo of extracellular vesicles. CONCLUSIONS: Including both supervised and unsupervised learning methods, as well as encompassing algorithms focused on both protein interaction and gene represent a comprehensive approach to tackle complex biomedical topics. DS-assisted methods for reviewing existent evidence, recommending targets of interest, and predicting original scenarios are worth exploring as in silico recommendations to be integrated with experts' ideas for optimizing molecular studies.

Comments on: Electromyographic signature of isometric squat in the highest refuge in Europe.

We read the comment by Sarabon and Sasek (Eur J Transl Myol 11846, 2023 doi: 10.4081/ejtm.2023.11846) on our study on the electromyographic results during squat at high-altitude. Their highlighting of the factors that may have biased our results is commendable, despite they criticized our work as if it were a controlled laboratory study. We considered the limitations and argued our interpretation with caution. We found no changes in median frequency, frequency's slope and conduction velocity of EMG signals at high altitude, and a slight decrease of root mean square. We argued that our results may have been due to a preventative mechanism that compensates for relatively greater effort during a fatiguing strength test involving large muscle masses, or to cumulative exertional stress on the muscles. The authors of the comment themselves somehow agree with these interpretations. Guidelines for collecting, reporting and interpreting data from EMG to obtain original information on the neuromuscular system should be integrated with the effort to maintain as much as possible those field conditions that offer unique opportunities.

Electromyographic signature of isometric squat in the highest refuge in Europe.

Reports of electromyography during hypoxic exercise are contrasting, due to protocol and muscle diversity. This work aimed to investigate alterations in muscle activation and myoelectrical fatigue during exercise at high-altitude in those muscles primarily involved in trekking. Twelve young adults balanced by gender and age were tested at low (1,667 m) and high (4,554 m, "Capanna Margherita", Italy) altitude, during an isometric squat lasting 60 seconds. High-density surface electromyography was performed from the quadriceps of right limb. The root mean square (RMS), median frequency with its slope, and muscle fiber conduction velocity (MFCV) were computed. Neither males nor females showed changes in median frequency (Med: 36.13 vs 35.63 Hz) and its slope (Med: -9 vs -12 degree) in response to high-altitude trekking, despite a great inter-individual heterogeneity, nor differences were found for MFCV. RMS was not significantly equivalent, with greater values at low altitude (0.385 ± 0.104 mV) than high altitude (0.346 ± 0.090 mV). Unexpected results can be due either to a postural compensation of the whole body compensating for a relatively greater effort or to the inability to support muscle activation after repeated physical efforts.  Interesting results may emerge by measuring simultaneously electromyography, muscle oxygenation and kinematics comparing trekking at normoxia vs hypoxia.

Clinical features and health-threatening conditions of the trek to Capanna Margherita.

BACKGROUND: Since trips to high altitude have become popular, reports on clinical and environmental characteristics during expeditions to popular destinations are needed. METHODS: A group of 15 healthy adults was monitored during a trek to Capanna Margherita (4556 m). A hypoxic stress test was applied before the expedition started. Environmental characteristics were acquired with a portable device. Vital signs were compared at low and high altitude, and altitude sickness was diagnosed by the Lake Louise scoring system. Ocular symptoms and intraocular pressure were recorded. RESULTS: Temperature ranged from -3.5 to 31.3 °C and relative humidity from 36 to 95% during the trek. Acute mountain sickness was diagnosed in 40% of participants, more frequently in women, and slightly associated with a greater drop in SpO2. Heart rate and blood pressure increased, while peripheral saturation and intraocular pressure decreased, in response to altitude hypoxia. CONCLUSIONS: Rapid ascents, as in the most common expedition plans, should be carefully supervised because of the common occurrence of AMS, especially in women. Among organ districts, the eye should deserve more attention in high-altitude medicine. Analyses of environmental conditions, together with predictive methods and early identification of health-threatening conditions, are of great value in supporting further recreational, professional and scientific expeditions to the most intriguing altitude sites.

Endurance-dependent urinary extracellular vesicle signature: shape, metabolic miRNAs, and purine content distinguish triathletes from inactive people.

Extracellular vesicles (EVs) enriched with bioactive molecules have gained considerable attention in nanotechnology because they are critical to intercellular communication while maintaining low immunological impact. Among biological matrices, urine has emerged as a noninvasive source of extracellular-contained liquid biopsy, currently of interest as a readout for physiological adaptations. Therefore, we aimed to evaluate chronic adaptations of endurance sport practice in terms of urinary EV parameters and evaluated by food consumption assessment. Two balanced groups of 13 inactive controls vs. triathlon athletes were enrolled; their urinary EVs were obtained by differential ultracentrifugation and analyzed by dynamic light scattering and transmission electron and atomic force microscopy. The cargo was analyzed by means of purine and miRNA content through HPLC-UV and qRT-PCR. Specific urinary EV signatures differentiated inactive versus endurance-trained in terms of peculiar shape. Particularly, a spheroid shape, smaller size, and lower roughness characterize EVs from triathletes. Metabolic and regulatory miRNAs often associated with skeletal muscle (i.e., miR378a-5p, miR27a-3p, miR133a, and miR206) also accounted for a differential signature. These miRNAs and guanosine in urinary EVs can be used as a readout for metabolic status along with the shape and roughness of EVs, novel informative parameters that are rarely considered. The network models allow scholars to entangle nutritional and exercise factors related to EVs' miRNA and purine content to depict metabolic signatures. All in all, multiplex biophysical and molecular analyses of urinary EVs may serve as promising prospects for research in exercise physiology.

Ventilatory function and oxygen delivery at high altitude in the Himalayas.

This study aimed to evaluate changes in lung function assessed by spirometry and blood gas content in healthy high-altitude sojourners during a trek in the Himalayas. A group of 19 Italian adults (11 males and 8 females, mean age 43 ± 15 years, and BMI 24.2 ± 3.7 kg/m2) were evaluated as part of a Mount Everest expedition in Nepal. Spirometry and arterial blood gas content were evaluated at baseline in Kathmandu (≈1400 m), at the Pyramid Laboratory - Observatory (peak altitude of ≈5000 m), and on return to Kathmandu 2-3 days after arrival at each site. All participants took 250 mg of acetazolamide per os once daily during the ascent. We found that arterial hemoglobin saturation, O2 and CO2 partial pressures, and the bicarbonate level all decreased (in all cases, p < 0.001 with R2 =0.70-0.90), while pHa was maintained stable at the peak altitude. Forced vital capacity (FVC) remained stable, while forced expiratory volume in 1 s (FEV1) decreased (p = 0.010, n2p =0.228), resulting in a lower FEV1/FVC ratio (p < 0.001, n2p =0.380). The best predictor for acute mountain sickness was the O2 partial pressure at the peak altitude (p = 0.004, R2 =0.39). Finger pulse oximetry overestimated peripheral saturation relative to arterial saturation. We conclude that high-altitude hypoxia alters the respiratory function and the oxygen saturation of the arterial blood hemoglobin. Additionally, air rarefaction and temperature reduction, favoring hypoxic bronchoconstriction, could affect respiration. Pulse oximetry seems not enough to assist medical decisions at high altitudes.

Investigating Auditory Perception at Europe's Highest Mountain Lodge.

Altitude hypoxia can impair sensory and cognitive functions, from causing slowed responses to sensory hallucinations. In a field study, we tested 12 expeditioners at varied altitudes (low: 1696 m; high: 4556 m) with a simple auditory detection task and a dichotic listening paradigm in which a voice was presented, lateralized, within a binaural white noise stream. Slower reaction times and a reduced right ear advantage might be expected at high (vs. low) altitude, due to hypoxia. The participants' performances on both tasks did not differ between conditions, revealing that these functions are resistant to short-term hypoxia in young healthy adults.

MicroRNA Expression in Subretinal Fluid in Eyes Affected by Rhegmatogenous Retinal Detachment.

Proliferative vitreoretinopathy (PVR) is an abnormal intraocular scarring process that can complicate cases of rhegmatogenous retinal detachment (RRD). Although previous studies have examined the relevance of microRNAs (miRNAs) in ophthalmic diseases, only a few studies have evaluated the expression profiles of microRNAs in subretinal fluid. We hypothesized that the expression profiles of specific miRNAs may change in response to RRD, in the subretinal fluid that is directly in contact with photoreceptors and the retinal pigment epithelium (RPE). We looked for a potential correlation between the expression of specific miRNAs in eyes with RRD and known clinical risk factors of PVR. A total of 24 patients (59 ± 11 years) who underwent scleral buckling procedure were enrolled in this prospective study. Twenty-four undiluted subretinal fluid samples were collected, RNA was isolated and qRT-PCR was performed to analyze the expression of 12 miRNAs. We found the existence of a positive association between the expression of miR-21 (p = 0.017, r = 0.515) and miR-34 (p = 0.030, r = 0.624) and the duration of symptoms related to retinal detachment. Moreover, the expression of miR-146a tended to decrease in patients who developed PVR. Subretinal fluid constitutes an intriguing biological matrix to evaluate the role of miRNAs leading to the development of PVR.

Intra- and Inter-Seasonal Fitness and Training Load Variations of Elite U20 Soccer Players.

Inherent physical and anthropometric traits of elite soccer players, influenced by nature and nurture, account for the emergence of performances across time. Purpose: The present study aimed to evaluate inter- and intraseasonal differences and the influence of playing position on training and fitness metrics in talented young soccer players. Methods: A total of 74 male players from U20 teams of a single elite club were tested both at beginning, during, and at the end of three consecutive competitive seasons. Players under went anthropometric measurement and were tested for aerobic, jumping, and sprinting performances; the GPS-derived measures of metabolic power (MP) and equivalent distance index (ED) of every athlete were analyzed. Results: Difference between teams emerged in Mognoni's test, while it did not in countermovement jump and anthropometrics. ED was different across seasons. The model selection criteria revealed that the Bosco-Vittori test achieved the best fit. BMI and countermovement jump (CMJ) increased, and fat mass decreased, during season; different intraseasonal trends for CMJ. MP was slightly greater in midfielder. Conclusion: Network approaches in modeling performance metrics in sports team could unveil original interconnections between performance factors. In addition, the authors support multiparametric longitudinal assessments and a huge database of sports data for facilitating talent identification.

Sports performance adaptations through occlusal splint: Case reports of triathlon athletes.

OBJECTIVE: Occlusal disturbances affect human posture and sports performance. This study aimed to monitor biomechanical adaptations to personalized occlusal splints. METHODS: Splints were customized based on stabilometry, thermography, sEMG, and kinesiography, and administered to three triathlon athletes. They were evaluated during a 4-month period, using isokinetic indexes, running kinematics and anaerobic outputs. RESULTS: Individuality emerged as a key factor driving type, quantity, quality, and time trajectories of adaptations. The use of instrumental and clinical tests allowed the detection of static balance and biting function improvements, but not necessarily parallel to sports performance improvements. CONCLUSION: The authors argue that strength and kinematic imbalances are joint and task-specific and support the use of multi-stage monitoring of the biomechanical effect of mouthpieces. Kinematics of cycling and running may be widely assessed with ecological and inexpensive methods. Strength imbalances need to be continuously monitored due to the high informative value to injury prevention.

Microbiota and Oral Cancer as A Complex and Dynamic Microenvironment: A Narrative Review from Etiology to Prognosis.

A complex balanced equilibrium of the bacterial ecosystems exists in the oral cavity that can be altered by tobacco smoking, psychological stressors, bad dietary habit, and chronic periodontitis. Oral dysbiosis can promote the onset and progression of oral squamous cell carcinoma (OSCC) through the release of toxins and bacterial metabolites, stimulating local and systemic inflammation, and altering the host immune response. During the process of carcinogenesis, the composition of the bacterial community changes qualitatively and quantitatively. Bacterial profiles are characterized by targeted sequencing of the 16S rRNA gene in tissue and saliva samples in patients with OSCC. Capnocytophaga gingivalis, Prevotella melaninogenica, Streptococcus mitis, Fusobacterium periodonticum, Prevotella tannerae, and Prevotella intermedia are the significantly increased bacteria in salivary samples. These have a potential diagnostic application to predict oral cancer through noninvasive salivary screenings. Oral lactic acid bacteria, which are commonly used as probiotic therapy against various disorders, are valuable adjuvants to improve the response to OSCC therapy.

Fertility Impairment after Trekking at High Altitude: A Proof of Mechanisms on Redox and Metabolic Seminal Changes.

Many authors described negative but reversible effects of high-altitude hypoxic exposure on animal and human fertility in terms of sperm concentration, function, and biochemical alterations. The aim of this study was to evaluate the acute and chronic effects of high-altitude exposure on classical sperm parameters, redox status, and membrane composition in a group of travellers. Five healthy Italian males, all lowlanders not accustomed to the altitude, were evaluated after 19 days-trekking through low, moderate, and high altitudes in the Himalayas. Sperm samples were collected before (Pre), 10 days after (Post), and 70 days after the end of the expedition (Follow-up). Sperm concentration, cholesterol and oxysterol membrane content, and redox status were measured. Hypoxic trek led to a significant reduction in sperm concentration (p < 0.001, η2p = 0.91), with a reduction from Pre to Post (71.33 ± 38.81 to 60.65 ± 34.63 × 106/mL) and a further reduction at Follow-up (to 37.13 ± 39.17 × 106/mL). The seminal volume was significantly affected by the hypoxic trek (p = 0.001, η2p = 0.75) with a significant reduction from Pre to Post (2.86 ± 0.75 to 1.68 ± 0.49 mL) and with partial recovery at Follow-up (to 2.46 ± 0.45 mL). Moreover, subjects had an increase in ROS production (+86%), and a decrease in antioxidant capacity (−37%) in the Post period with partial recovery at Follow-up. These results integrated the hormonal response on thyroid function, hypothalamus−pituitary−gonadal axis, and the prolactin/cortisol pathways previously reported. An uncontrolled ROS production, rather than a compromised antioxidant activity, was likely the cause of impaired sperm quality. The reduction in fertility status observed in this study may lie in an evolutionary Darwinian explanation, i.e., limiting reproduction due to the "adaptive disadvantage" offered by the combined stressors of high-altitude hypoxia and daily physical exercise.

Redox-based Disruption of Cellular Hormesis and Promotion of Degenerative Pathways: Perspectives on Aging Processes.

The present work aims to link the redox and cell-centric theories of chronic processes in human biology, focusing on aging. A synthetic overview of cellular redox pathways will be integrated by the concept of hormesis, which disruption leads to several physiopathological processes. The onset of age-related diseases due to the restriction of homeodynamic capacity will be herein considered in a redox fashion. Up-to-date arguments on hormetic agents, such as geroprotectors, dietary interventions, and physical exercise are refining the presented theoretical framework, integrated by insights from extracellular vesicles, microbiota, pollutants, and timing mechanisms. The broad concepts of exposome encompass the redox-based alteration of cellular hormesis for providing meaningful perspectives on redox biogerontology.

New Perspectives for Postmortem Human Satellite Cells of Different Embryological Origin.

Human postmortem skeletal muscles are a unique source of satellite cells for skeletal muscle regenerative studies. Presomite and somite satellite cells obtained by postmortem muscles have been established as populations of human skeletal muscle precursor cells able to proliferate and differentiate in vitro. It is extremely interesting to have access to a large amount of postmortem human skeletal muscle precursor cells, especially from craniofacial as well as limb skeletal muscles in order to evaluate their potential application not only for the fundamental understanding of muscle physiology and diseases but also for drug testing in a challenging 3D-shaping muscles like skeletal muscle microphysiological systems.