Editorial for the Special Issue "Molecular Bases of Senescence".

The increasing life expectancy of populations worldwide represents the most evident success of the last century thanks to varying interacting social and medical achievements [...].

Biological Aspects of Selected Myokines in Skeletal Muscle: Focus on Aging.

In the last decade, clear evidence has emerged that the cellular components of skeletal muscle are important sites for the release of proteins and peptides called "myokines", suggesting that skeletal muscle plays the role of a secretory organ. After their secretion by muscles, these factors serve many biological functions, including the exertion of complex autocrine, paracrine and/or endocrine effects. In sum, myokines affect complex multi-organ processes, such as skeletal muscle trophism, metabolism, angiogenesis and immunological response to different physiological (physical activity, aging, etc.) or pathological states (cachexia, dysmetabolic conditions, chronic inflammation, etc.). The aim of this review is to describe in detail a number of myokines that are, to varying degrees, involved in skeletal muscle aging processes and belong to the group of proteins present in the functional environment surrounding the muscle cell known as the "Niche". The particular myokines described are those that, acting both from within the cell and in an autocrine manner, have a defined relationship with the modulation of oxidative stress in muscle cells (mature or stem) involved in the regulatory (metabolic or regenerative) processes of muscle aging. Myostatin, IGF-1, NGF, S100 and irisin are examples of specific myokines that have peculiar features in their mechanisms of action. In particular, the potential role of one of the most recently characterized myokines-irisin, directly linked to an active lifestyle-in reducing if not reversing senescence-induced oxidative damage is discussed in terms of its possible application as an agent able to counteract the deleterious effects of muscle aging.

Guanosine-Based Nucleotides, the Sons of a Lesser God in the Purinergic Signal Scenario of Excitable Tissues.

Purines are nitrogen compounds consisting mainly of a nitrogen base of adenine (ABP) or guanine (GBP) and their derivatives: nucleosides (nitrogen bases plus ribose) and nucleotides (nitrogen bases plus ribose and phosphate). These compounds are very common in nature, especially in a phosphorylated form. There is increasing evidence that purines are involved in the development of different organs such as the heart, skeletal muscle and brain. When brain development is complete, some purinergic mechanisms may be silenced, but may be reactivated in the adult brain/muscle, suggesting a role for purines in regeneration and self-repair. Thus, it is possible that guanosine-5'-triphosphate (GTP) also acts as regulator during the adult phase. However, regarding GBP, no specific receptor has been cloned for GTP or its metabolites, although specific binding sites with distinct GTP affinity characteristics have been found in both muscle and neural cell lines. Finally, even if the cross regulation mechanisms between the two different purines (ABP and GBP) are still largely unknown, it is now possible to hypothesize the existence of specific signal paths for guanosine-based nucleotides that are capable of modulating the intensity and duration of the intracellular signal, particularly in excitable tissues such as brain and muscle.

Determination of blood lactate training zone boundaries with rating of perceived exertion in runners.

This study aimed to determine the rating of perceived exertion (RPE) values corresponding to the blood lactate concentration (BLC) training zone boundaries (2 and 4 mmol·L) in moderately trained runners using the Borg CR-10 scale. Moderately trained runners (n = 95) performed a submaximal incremental test on a treadmill, recording BLC and RPE at every stage. Simple linear regression analysis was used to determine the RPE values corresponding to the BLC training zone boundaries, which revealed that RPE was significantly and strongly correlated with BLC (r = 0.821, p < 0.001, R = 0.675, adjusted R = 0.674, standard error of estimate = 1.18). The prediction equation (RPE = 1.092 × BLC + 2.143) was obtained, and RPE values at the BLC training zone boundaries of 2 and 4 mmol·L were calculated as 4.3 (95% confidence interval [CI], 3.9-4.7) and 6.5 (95% CI, 6.0-7.1), respectively. In conclusion, the RPE values at the BLC training zone boundaries of 2 mmol·L (4.3) and 4 mmol·L (6.5) were adequately predicted. Rating of perceived exertion (4.3 and 6.5) can be used as an affordable tool for controlling intensity to maintain the athletes in prescribed zones during training sessions.

Extracellular GTP is a potent water-transport regulator via aquaporin 5 plasma-membrane insertion in M1-CCD epithelial cortical collecting duct cells.

BACKGROUND/AIMS: Extracellular GTP is able to modulate some specific functions in neuron, glia and muscle cell models as it has been demonstrated over the last two decades. In fact, extracellular GTP binds its specific plasma membrane binding sites and induces signal transduction via [Ca(2+)]i increase. We demonstrate, for the first time, that extracellular GTP is able to modulate cell swelling in M1-CCD cortical collecting duct epithelial cells via upregulation of aquaporin 5 (AQP5) expression. METHODS: We used videoimaging, immunocitochemistry, flow cytometry, confocal techniques, Western blotting and RT-PCR for protein and gene expression analysis, respectively. RESULTS: We demonstrate that AQP5 mRNA is up-regulated 7 h after the GTP exposure in the cell culture medium, and its protein level is increased after 12-24 h. We show that AQP5 is targeted to the plasma membrane of M1-CCD cells, where it facilitates cell swelling, and that the GTP-dependent AQP5 up-regulation occurs via [Ca(2+)]i increase. Indeed, GTP induces both oscillating and transient [Ca(2+)]i increase, and specifically the oscillating kinetic appears to be responsible for blocking cell cycle in the S-phase while the [Ca(2+)]i influx, with whatever kinetic, seems to be responsible for inducing AQP5 expression. CONCLUSION: The role of GTP as a regulator of AQP5-mediated water transport in renal cells is of great importance in the physiology of renal epithelia, due to its possible physiopathological implications. GTP-dependent AQP5 expression could act as osmosensor. In addition, the data presented here suggest that GTP might play the same role in other tissues where rapid water transport is required for cell volume regulation and maintenance of the homeostasis.

Dirk Pette, remembered for his pioneering muscle research.

It is with great sadness that we learned of the passing of Prof. Dr. Dr. h.c. Dirk Pette. He passed away suddenly and unexpectedly on June 4, 2022. Dirk was an outstanding professor of biochemistry at the University of Konstanz, Germany and an internationally renowned researcher in the field of skeletal muscle biology. His research on electrical stimulation has had a profound impact on our understanding of myofiber type specification and the enormous adaptive potential of skeletal muscle. Under Dirk's leadership, new biological questions in the field of neuromuscular biology have developed into multidisciplinary approaches using advanced physiological, cell biological, and biochemical techniques. Dirk's research laboratory was frequently visited by a large number of national and international collaborators who familiarized themselves with the technically demanding stimulation protocols and bioanalytical techniques to study the intricate details of the highly complex process of fast-to-slow muscle transitions. Importantly, fundamental studies on the physiological effects of changes in innervation patterns on muscle phenotype have provided the scientific evidence base for a variety of innovative clinical applications. The skeletal muscle research community has lost one of its leading figures and an outstanding teacher of protein biochemistry. He leaves an inspiring legacy in the field of basic and applied myology. Dirk will be missed by his colleagues and by many students of neuromuscular biology and beyond.

Physical Activity Effects on Muscle Fatigue in Sport in Active Adults with Long COVID-19: An Observational Study.

Long COVID-19-related changes in physiology includes alterations in performing muscle work as fatigue. Data available do not allow us to define the usefulness of physical activity to attenuate long COVID-19 functional modifications. The present observational study investigates the effects of physical activity on the perception of fatigue, maximum power output, sleep, and cognitive modifications in subjects affected by long COVID-19, distinguishing between active and sedentary subjects. The data demonstrated the following: the perception of fatigue 1 year after the end of virus positivity was significantly reduced with respect to that observed after 6 months by more than 50% more in active subjects compared to sedentary ones; 6 months after the end of virus positivity, the force developed by active subjects was reduced (RM factor: p < 0.001, η2p = 0.527, post hoc: p < 0.001), but the reduction was more pronounced in sedentary ones (mean difference = 38.499 W); poor sleep quality and mild cognitive impairment were assessed in both active and sedentary subjects. In conclusion, the study suggests that the long COVID-19 fatigue was lower in active subjects respect to sedentary ones. A comparative analysis performed due to the overlap of functional alterations between long COVID-19 and ME/CFS showed that in a small percentage of the enrolled subjects (8%), the symptomatology reflected that of ME/CFS and was independent of the individual physical capacities.

Comments on: Effect of physical activity on long COVID fatigue.

The authors of the Comments on: Effect of physical activity on long COVID fatigue by Daungsupawong F. and Wiwanitkit V. (2023) have highlighted certain aspects of future research that need to be considered before any conclusions can be drawn regarding the effect of previous physical activity and/or fitness on the course of long-COVID. We can only agree with this need, although we hope that the effects of SARS-CoV-2 infection will become less and less burdensome to manage. As we hypothesise in the last part of the article by Coscia et al. (2023), we think it is crucial to identify the molecular mechanism underlying the atrophic effect (if any) of the described disease states, which could originate from a local inflammatory storm induced by Spike binding to the ACE-2 receptor in muscle. When studies on muscle from patients will be available in sufficient numbers, we will be able to try to answer the still open questions.

Effect of physical activity on long COVID fatigue: an unsolved enigma.

Covid-19 disease is well documented and often the most common symptoms include myalgia and muscle fatigue. Approximately 10% of those infected complain of persistent fatigue even many months after the end of the acute phase of the disease. This gives rise to a condition different from the previous one and commonly known as 'post-acute COVID-19 syndrome' or simply Long-COVID. Although the origin of muscle fatigue is multifactorial, the state of prolonged fatigue observed in the Long-COVID syndrome suggests the existence of a possible state of atrophy or rather acute sarcopenia. Under these conditions, the use of physical activity programs can effectively counteract the state of atrophy underlying the fatigue phenomena observed. If this is also the situation during the Long-COVID, the muscular symptom should be positively influenced by the administration of programmed physical activity cycles. In fact, in patients with Long-COVID, the few published papers seem to indicate that patients who are physically active and who make an effort to engage in physical activity even during the illness have decreased duration and intensity of the illness. However, analysis of the studies in the literature also suggests that a small percentage of people with Long-COVID do not appear to benefit from the application of physical activity programs, so further studies on homogeneous samples are needed to provide a firm answer to the question: can planned physical activity help patients during the pathological course of Long-COVID?

Oxidative Stress in Skeletal Muscle.

The accumulation of ROS, mainly due to increased mitochondrial production and/or decreased scavenger systems, is often associated with the term oxidative stress, used to define a condition judged to be problematic for muscle cells [...].

H2O2/Ca2+/Zn2+ Complex Can Be Considered a "Collaborative Sensor" of the Mitochondrial Capacity?

In order to maintain a state of well-being, the cell needs a functional control center that allows it to respond to changes in the internal and surrounding environments and, at the same time, carry out the necessary metabolic functions. In this review, we identify the mitochondrion as such an "agora", in which three main messengers are able to collaborate and activate adaptive response mechanisms. Such response generators, which we have identified as H2O2, Ca2+, and Zn2+, are capable of "reading" the environment and talking to each other in cooperation with the mitochondrion. In this manner, these messengers exchange information and generate a holistic response of the whole cell, dependent on its functional state. In this review, to corroborate this claim, we analyzed the role these actors, which in the review we call "sensors", play in the regulation of skeletal muscle contractile capacities chosen as a model of crosstalk between Ca2+, Zn2+, and H2O2.

Effects of a vibrational proprioceptive stimulation on recovery phase after maximal incremental cycle test.

Global Proprioceptive Resonance (GPR) is a recently developed approach conceived to solicit the various cutaneous mechanoreceptors, through application of mechanical multifocal vibration at low amplitude and at definite body sites, limiting the stimulation of the profound structures. This interventional study evaluated the effects of GPR on cardiorespiratory function during the post-exertional recovery period. A group of volunteers involved in Triathlon (a multisport discipline consisting of sequential swim, cycle, and run disciplines higly demanding in terms of metabolic engagment), underwent two maximal incremental exercise tests until exhaustion followed alternatively to (a) a 13 minutes section of GPR or (b) a standard low intensity exercise acute trend of the same duration. These effects of these two approaches were compared in terms of recovery of: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2) and venous lactate concentration (Lac). The physiological parameters (HR, RR, SpO2 and Lac) recorded in the pre-exertion session showed similar values between the 40 volunteers while several differences were recorded in the post-exertion phase. After 6 min of GPR recovery it was recorded a drop in RR below baseline (19.4±4.15 min-1 vs. 12.2± 0.4 min-1; p<0.001) coupled with an increase in peripheral oxygen saturation above the baseline (GPR: 99.0%±0.16% vs. 96.6%±0.77%, p<0.001). Moreover, the most striking result was the drop in lactate concentration measured after 13 min of GPR recovery: 84.5±3.5% in GPR vs 2.9±7.6% reduction in standard recovery (p<0.001). Notably no differences were recorded recovery of heart rate. GPR has promising effects on post-exercise recovery on RR, SpO2 and lactate level on young athletes.

Sport medicine and safety at work.

As humans become more and more sedentary, physical capacities also become lost along with aerobic fitness, muscular strength, coordination, and action-reaction time. This situation can lead to not only absence from work (back pain is the most common reason in European Union (EU), but especially, workplace accidents. In this article, we want to combine our experience with exercise physiology and physical capacities with our medical work in a critical environment. We tested over ten years, the fitness profile of 1200 Italian Alpine Soldiers, and gave them a scientific training program. We obtained a trained and homogeneous team (homogeneous, in terms of aerobic and anaerobic fitness). Here, we detail changes to aerobic and anaerobic fitness resulting because of soldiers' participation in a training program. We consider this method necessary for safe work in a critical environment.

The Arianna thread: the matching of S-100 family with the RyR's muscle receptor.

The functional state of RyR depends on the intracellular calcium concentration and on the oxidation state of its protein components in some particular sites and of some sentinel amino acids. In addition to the regulation of the RyR channel by exogenous substances (caffeine, ryanodine), ions environmental situations (oxidative state), other components, such as some endogenous proteins present in the sarcoplasm and/or in muscle membranes that are able to determine changes in Ca2+ channel activity. Among these, calmodulin and S-100A could determine modifications in the status of RyR channel in the skeletal muscle. The currently available data can be justified the use of a simplified S-100/CaM and RyR interaction model for the regulation of Ca2+ release in skeletal muscle. Under resting conditions, the CaM/S100A1 binding domain on RyR1 is predominantly dependent on S100A1. Vice versa when the intracellular Ca2+ concentration becomes high as well as during repetitive (tetanus) stimulation, the Ca-CaM bond becomes dominant, shifting S100A1 from RyR1 and promoting channel inactivation. This may be one of the mechanism of muscle fatigue.

Effects of a vibrational proprioceptive stimulation on recovery phase after maximal incremental cycle test.

Global Proprioceptive Resonance (GPR) is a recently developed approach conceived to solicit the various cutaneous mechanoreceptors, through application of mechanical multifocal vibration at low amplitude and at definite body sites, limiting the stimulation of the profound structures. This interventional study evaluated the effects of GPR on cardiorespiratory function during the post-exertional recovery period. A group of volunteers involved in Triathlon (a multisport discipline consisting of sequential swim, cycle, and run disciplines higly demanding in terms of metabolic engagment), underwent two maximal incremental exercise tests until exhaustion followed alternatively to (a) a 13 minutes section of GPR or (b) a standard low intensity exercise acute trend of the same duration. These effects of these two approaches were compared in terms of recovery of: heart rate (HR), respiratory rate (RR), peripheral oxygen saturation (SpO2) and venous lactate concentration (Lac). The physiological parameters (HR, RR, SpO2 and Lac) recorded in the pre-exertion session showed similar values between the 40 volunteers while several differences were recorded in the post-exertion phase. After 6 min of GPR recovery it was recorded a drop in RR below baseline (19.4±4.15 min-1 vs. 12.2± 0.4 min-1; p<0.001) coupled with an increase in peripheral oxygen saturation above the baseline (GPR: 99.0%±0.16% vs. 96.6%±0.77%, p<0.001). Moreover, the most striking result was the drop in lactate concentration measured after 13 min of GPR recovery: 84.5±3.5% in GPR vs 2.9±7.6% reduction in standard recovery (p<0.001). Notably no differences were recorded recovery of heart rate. GPR has promising effects on post-exercise recovery on RR, SpO2 and lactate level on young athletes.

Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome.

The chronic fatigue syndrome (CFS) otherwise known as myalgic encephalomyelitis (ME), is a debilitating syndrome whose identification is very complex due to lack of precise diagnostic criteria. This pathology begins with limitations in duration and intensity of exercise and rapid onset of pain during physical activity. Its etiology is unknown, and symptoms are not limited to the muscles. Epidemiology is rather difficult to delimit, even if it affects mainly young (20-40 years), female subjects. The results of muscular research show some peculiarities that can justify what has been observed in vivo. In particular, 1. presence of oxidative damage of lipid component of biological membranes and DNA not compensated by the increase of the scavenger activity; 2. Excitation-Contraction (E-C) alteration with modification of Ca2+ transport; 3. passage from slow to fast fiber phenotype; 4. inability to increase glucose uptake; 5. presence of mitochondrial dysfunction; and 6. genes expressed differentially (particularly those involved in energy production). The skeletal muscles of CFS / ME patients show a significant alteration of the oxidative balance due to mitochondrial alteration and of the fiber phenotype composition as shown in sarcopenic muscles of the elderly. Vice versa, the muscle catabolism does not appear to be involved in the onset of this syndrome. The data support the hypothesis that patients with CFS are subjected to some of the problems typical for muscle aging, which is probably related to disorders of muscle protein synthesis and biogenesis of mitochondria. Patients with CFS can benefit from an appropriate training program because no evidence suggests that physical exercise worsens symptoms. Type, intensity and duration of any physical activity that activates muscle contraction (including Electrical Stimulation) require further investigation even if it is known that non-exhaustive physical activity decreases painful symptomatology.

Physiological effects of high-altitude trekking on gonadal, thyroid hormones and macrophage migration inhibitory factor (MIF) responses in young lowlander women.

Altitude hypoxia is often associated with impairment of human reproduction. In this study, hormones and macrophage migration inhibitory factor (MIF, a proinflammatory cytokine with key roles in human reproduction) were determined in seven regularly menstruating, lowlander native women living at sea level participating in 14 days of trekking at moderate and high altitude. Blood and saliva samples were collected from each subject at high altitude (5050 m a.s.l. [above sea level]), and at sea level before and after the expedition. Testosterone level was lowered by high altitude and was restored after the end of the expedition, while progesterone decreased significantly in all participants at the end of the expedition, although most of the participants were in the luteal phase. The salivary concentration of MIF decreased greatly at altitude, but its levels were completely restored after the return to sea level. Our findings showed high sensitivity and rapid changes in the determined parameters in response to the high-altitude hypoxic environment, particularly MIF.

Psychological and Physiological Processes in Figure-Tracing Abilities Measured Using a Tablet Computer: A Study with 7 and 9 Years Old Children.

The present study investigated the use of a tablet computer to assess figure-tracing skills and their relationships with psychological (visual-perceptual processes, cognitive processes, handwriting skills) and physiological (body mass index, isometric strength of arms) parameters with school-children of second (7-8-year-olds) and fourth (9-10-year-olds) grades. We were also interested in gender differences. The task required tracing of geometric figures on a template, shown on a tablet screen in light gray, for the segments that make up the target figure, one at a time. This figure-tracing tablet test allows acquisition and automated analysis of four parameters: number of strokes (pen lift) for each segment; oscillations of lines drawn with respect to reference lines; pressure of pen on tablet; and average speed of tracing. The results show a trade-off between speed and quality for the tablet parameters, with higher speed associated with more oscillations with respect to the reference lines, and lower number of strokes for each segment, in both male and female children. The involvement of visual-motor integration on the ability to reduce the oscillations in this tablet test was only seen for the male children, while both the male and female children showed a relationship between oscillations and more general/abstract visual-spatial processes. These data confirm the role of visual-motor processes in this figure-tracing tablet test only for male children, while more general visual-spatial processes influence the performance in the tablet test for both sexes. We conclude that the test proposed is useful to screen for grapho-motor difficulties.

Analysis of Training Load and Competition During the PhD Course of a 3000-m Steeplechase Female Master Athlete: An Autobiography.

The first author, Elisa Gabrielli, has been a distance runner for many years, and then at a particular point in her career, she decided to move over to the 3000-m steeplechase. She was attracted by this discipline as she believed that it would be the appropriate discipline for her, due to the challenge it provided her, and the necessary knowledge and awareness she had through her studies. For reasons that are discussed in this report, the 3000-m steeplechase is a race that is more difficult to interpret and manage biomechanically and physiologically than most others. Combining this with her PhD allowed her to use a multidisciplinary approach to review the competitive experience gained in this discipline. During this period, she indeed not only deepened the technical aspects of her training, but also those that underlie this discipline, through her knowledge of sport, with particular reference to the female athlete. Through her technical research, she was able to take 'snapshots' of what could happen from the physiological point of view. With satisfaction, she improved her performance in the 3000-m race and in the 3000-m steeplechase. How? In particular, she worked on her running technique through specific exercises. She worked on de-contraction and posture, while saving energy consumption. She worked on the control of her breathing, and she took into account her prevailing heart rate. This was all in combination with the consumption of specific nutrients, as she tried to manage the production of lactate with the training of the red muscle fibres that are rich in mitochondria. Finally, she tried to improve her perception of strenuous work, by training at high altitude. This allowed her not only to improve her physical performance, but especially to improve her mind-set, which allowed her to be more confident in herself and her abilities.

The role of general dynamic coordination in the handwriting skills of children.

Difficulties in handwriting are often reported in children with developmental coordination disorder, and they represent an important element in the diagnosis. The present study was aimed at investigating the relation between motor coordination and handwriting skills, and to identify differences in handwriting between children without and with coordination difficulties. In particular, we asked whether visual-spatial skills have a role as mediating variables between motor coordination and handwriting. We assessed motor coordination as well as graphic abilities in children aged 7-10 years. Moreover, we evaluated their visual-motor integration, visual-spatial skills, and other cognitive abilities (memory and planning). We found no relation between motor coordination and handwriting skills, while visual-spatial skills (measured by a visual-constructive task) were related with both. Our conclusion is that visual-spatial skills are involved both in general motor coordination and in handwriting, but the relationship involves different aspects in the two cases.