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The importance of sports and the approval of the Dual Career regulation at the University of Rome "Tor Vergata" are highly significant topics for the well-being and personal development of students. In line with European and international policies, this initiative recognizes the specific needs of student-athletes by offering them tools and flexibility to excel in both sports and academics. However, monitoring student-athletes by Universities requires thorough investigations and the development of initiatives to promote students' adherence to sports practice. Therefore, our study aims to analyze the results of a survey administered to students enrolled at the University of Rome "Tor Vergata" during the academic years 2020/2021, 2021/2022, 2022/2023, and 2023/2024, investigating the effects of the introduction of the Dual Career regulation on the student population. Our preliminary results showed that the introduction of the Dual Career program was associated with a significant increase in the number of students practising sports over the academic years, with greater participation in the academic years 2022/2023 and 2023/2024. Noteworthy, the number of student-athletes who applied to the Dual Career program markedly increased in the last year, with the highest number of enrollments in the macroareas of Medicine and Surgery, Economy, and Engineering. Overall, the Dual Career regulation offers the possibility to plan the study path in a personalized way, dedicated academic support, and flexibility in deadlines, making the University of Rome "Tor Vergata" a model of integration between education and sportiness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Cariati, Bonanni, Onorati and Tancredi.)

The aging of the world population is closely associated with an increased prevalence of musculoskeletal disorders, such as osteoporosis, sarcopenia, and osteoarthritis, due to common genetic, endocrine, and mechanical risk factors. These conditions are characterized by degeneration of bone, muscle, and cartilage tissue, resulting in an increased risk of fractures and reduced mobility. Importantly, a crucial role in the pathophysiology of these diseases has been proposed for cellular senescence, a state of irreversible cell cycle arrest induced by factors such as DNA damage, telomere shortening, and mitochondrial dysfunction. In addition, senescent cells secrete pro-inflammatory molecules, called senescence-associated secretory phenotype (SASP), which can alter tissue homeostasis and promote disease progression. Undoubtedly, targeting senescent cells and their secretory profiles could promote the development of integrated strategies, including regular exercise and a balanced diet or the use of senolytics and senomorphs, to improve the quality of life of the aging population. Therefore, our review aimed to highlight the role of cellular senescence in age-related musculoskeletal diseases, summarizing the main underlying mechanisms and potential anti-senescence strategies for the treatment of osteoporosis, sarcopenia, and osteoarthritis.

Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-increasing population incidence. Particularly, Alzheimer's disease (AD) is the most widespread ND characterized by an accumulation of amyloid aggregates of beta-amyloid (Aβ) and Tau proteins that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques are needed to diagnose AD, the investigation of biomarkers within body fluids could provide important information on neurodegeneration. Indeed, as there is no definitive solution for AD, the monitoring of these biomarkers is of strategic importance as they are useful for both diagnosing AD and assessing the progression of the neurodegenerative state. In this context, exercise is known to be an effective non-pharmacological management strategy for AD that can counteract cognitive decline and neurodegeneration. However, investigation of the concentration of fluid biomarkers in AD patients undergoing exercise protocols has led to unclear and often conflicting results, suggesting the need to clarify the role of exercise in modulating fluid biomarkers in AD. Therefore, this critical literature review aims to gather evidence on the main fluid biomarkers of AD and the modulatory effects of exercise to clarify the efficacy and usefulness of this non-pharmacological strategy in counteracting neurodegeneration in AD.

Neuronal death could be responsible for the cognitive impairments found in astronauts exposed to spaceflight, highlighting the need to identify potential countermeasures to ensure neuronal health in microgravity conditions. Therefore, differentiated HT22 cells were exposed to simulated microgravity by random positioning machine (RPM) for 48 h, treating them with a single administration of Trolox, recombinant irisin (r-Irisin) or both. Particularly, we investigated cell viability by MTS assay, Trypan Blue staining and western blotting analysis for Akt and B-cell lymphoma 2 (Bcl-2), the intracellular increase of reactive oxygen species (ROS) by fluorescent probe and NADPH oxidase 4 (NOX4) expression, as well as the expression of brain-derived neurotrophic factor (BDNF), a major neurotrophin responsible for neurogenesis and synaptic plasticity. Although both Trolox and r-Irisin manifested a protective effect on neuronal health, the combined treatment produced the best results, with significant improvement in all parameters examined. In conclusion, further studies are needed to evaluate the potential of such combination treatment in counteracting weightlessness-induced neuronal death, as well as to identify other potential strategies to safeguard the health of astronauts exposed to spaceflight., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bonanni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Space colonization represents the most insidious challenge for mankind, as numerous obstacles affect the success of space missions. Specifically, the absence of gravitational forces leads to systemic physiological alterations, with particular emphasis on the musculoskeletal system. Indeed, astronauts exposed to spaceflight are known to report a significant impairment of bone microarchitecture and muscle mass, conditions clinically defined as osteoporosis and sarcopenia. In this context, space medicine assumes a crucial position, as the development of strategies to prevent and/or counteract weightlessness-induced alterations appears to be necessary. Furthermore, the opportunity to study the biological effects induced by weightlessness could provide valuable information regarding adaptations to spaceflight and suggest potential treatments that can preserve musculoskeletal health under microgravity conditions. Noteworthy, improving knowledge about the latest scientific findings in this field of research is crucial, as is thoroughly investigating the mechanisms underlying biological adaptations to microgravity and searching for innovative solutions to counter spaceflight-induced damage. Therefore, this narrative study review, performed using the MEDLINE and Google Scholar databases, aims to summarize the most recent evidence regarding the effects of real and simulated microgravity on the musculoskeletal system and to discuss the effectiveness of the main defence strategies used in both real and experimental settings.

Osteosarcopenia (OSP) is a geriatric syndrome characterized by the coexistence of osteoporosis and sarcopenia and associated with an increased risk of fragility fractures, disability, and mortality. For patients with this syndrome, musculoskeletal pain represents the most significant challenge since, in addition to limiting the individual's functionality and promoting disability, it has a huge psychological burden involving anxiety, depression, and social withdrawal. Unfortunately, the molecular mechanisms involved in the development and persistence of pain in OSP have not yet been fully elucidated, although immune cells are known to play a key role in these processes. Indeed, they release several molecules that promote persistent inflammation and nociceptive stimulation, resulting in the gating of ion channels responsible for the generation and propagation of the noxious stimulus. The adoption of countermeasures to counteract the OSP progression and reduce the algic component appears to be necessary, providing patients with a better quality of life and greater adherence to treatment. In addition, the development of multimodal therapies, based on an interdisciplinary approach, appears to be crucial, combining the use of anti-osteoporotic drugs with an educational programme, regular physical activity, and proper nutrition to eliminate risk factors. Based on this evidence, we conducted a narrative review using the PubMed and Google Scholar search engines to summarize the current knowledge on the molecular mechanisms involved in the pain development in OSP and the potential countermeasures to be taken. The lack of studies addressing this topic highlights the need to conduct new research into the resolution of an ever-expanding social problem.

Spaceflight exposure, like prolonged skeletal unloading, is known to result in significant bone loss, but the molecular mechanisms responsible are still partly unknown. This impairment, characterizing both conditions, suggests the possibility of identifying common signalling pathways and developing innovative treatment strategies to counteract the bone loss typical of astronauts and osteoporotic patients. In this context, primary cell cultures of human osteoblasts derived from healthy subjects and osteoporotic patients were exposed to random positioning machine (RPM) to reproduce the absence of gravity and to exacerbate the pathological condition, respectively. The duration of exposure to RPM was 3 or 6 days, with the aim of determining whether a single administration of recombinant irisin (r-irisin) could prevent cell death and mineralizing capacity loss. In detail, cellular responses were assessed both in terms of death/survival, by MTS assay, analysis of oxidative stress and caspase activity, as well as the expression of survival and cell death proteins, and in terms of mineralizing capacity, by investigating the pentraxin 3 (PTX3) expression. Our results suggest that the effects of a single dose of r-irisin are maintained for a limited time, as demonstrated by complete protection after 3 days of RPM exposure and only partial protection when RPM exposure was for a longer time. Therefore, the use of r-irisin could be a valid strategy to counteract the bone mass loss induced by weightlessness and osteoporosis. Further studies are needed to determine an optimal treatment strategy based on the use of r-irisin that is fully protective even over very long periods of exposure and/or to identify further approaches to be used in a complementary manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cariati, Bonanni, Rinaldi, Marini, Iundusi, Gasbarra, Tancredi and Tarantino.)

Background: Osteoporosis is a complex multifactorial disease characterized by reduced bone mass and microarchitectural deterioration of bone tissue linked to an increase of fracture risk. Fragility fractures occur in osteoporotic subjects due to low-energy trauma. Osteoporotic patients are a challenge regarding the correct surgical planning, as it can include fixation augmentation techniques to reach a more stable anchorage of the implant, possibly lowering re-intervention rate and in-hospital stay., Methods: The PubMed database and the Google Scholar search engine were used to identify articles on all augmentation techniques and their association with fragility fractures until January 2022. In total, we selected 40 articles that included studies focusing on humerus, hip, spine, and tibia., Results: Literature review showed a quantity of materials that can be used for reconstruction of bone defects in fragility fractures in different anatomic locations, with good results over the stability and strength of the implant anchorage, when compared to non-augmented fractures., Conclusion: Nowadays there are no recommendations and no consensus about the use of augmentation techniques in osteoporotic fractures. Our literature review points at implementing the use of bone augmentation techniques with a specific indication for elderly patients with comminuted fractures and poor bone quality., (© 2022. The Author(s).)

Osteoporotic fractures are one of the major problems facing healthcare systems worldwide. Undoubtedly, fragility fractures of the hip represent a far greater burden in terms of morbidity, mortality, and healthcare costs than other fracture sites. However, despite the significant impact on the health and quality of life of older adults, there is a general lack of awareness of osteoporosis, which results in suboptimal care. In fact, most high-risk individuals are never identified and do not receive adequate treatment, leading to further fragility fractures and worsening health status. Furthermore, considering the substantial treatment gap and the proven cost-effectiveness of fracture prevention programs such as Fracture Liaison Services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are adequately assessed and treated. Based on this evidence, the aim of our review was to (i) provide an overview and comparison of the burden and management of fragility fractures, highlighting the main gaps, and (ii) highlight the importance of using alternative approaches, both surgical and non-surgical, with the aim of implementing early prevention of osteoporotic fractures and improving the management of osteoporotic patients at imminent and/or very high risk of fracture., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Osteosarcopenia (OS) is a newly defined condition represented by the simultaneous presence of osteopenia/osteoporosis and sarcopenia, the main age-related diseases. The simultaneous coexistence of the two phenotypes derives from the close connection of the main target tissues involved in their pathogenesis: bone and muscle. These two actors constitute the bone-muscle unit, which communicates through a biochemical and mechanical crosstalk which involves multiple factors. Altered pattern of molecular pathways leads to an impairment of both the functionality of the tissue itself and the communication with the complementary tissue, composing the OS pathogenesis. Recent advances in the genetics field have provided the opportunity to delve deeper into the complex biological and molecular mechanisms underlying OS. Unfortunately, there are still many gaps in our understanding of these pathways, but it has proven essential to apply strategies such as exercise and nutritional intervention to counteract OS. New therapeutic strategies that simultaneously target bone and muscle tissue are limited, but recently new targets for the development of dual-action drug therapies have been identified. This narrative review aims to provide an overview of the latest scientific evidence associated with OS, a complex disorder that will pave the way for future research aimed at understanding the bone-muscle-associated pathogenetic mechanisms., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Several studies agree that mechanical vibration can induce physiological changes at different levels, improving neuromuscular function through postural control strategies, muscle tuning mechanisms and tonic vibration reflexes. Whole-body vibration has also been reported to increase bone mineral density and muscle mass and strength, as well as to relieve pain and modulate proprioceptive function in patients with osteoarthritis or lower back pain. Furthermore, vibratory training was found to be an effective strategy for improving the physical performance of healthy athletes in terms of muscle strength, agility, flexibility, and vertical jump height. Notably, several benefits have also been observed at the brain level, proving to be an important factor in protecting and/or preventing the development of age-related cognitive disorders. Although research in this field is still debated, certain molecular mechanisms responsible for the response to whole-body vibration also appear to be involved in physiological adaptations to exercise, suggesting the possibility of using it as an alternative or reinforcing strategy to canonical training. Understanding these mechanisms is crucial for the development of whole body vibration protocols appropriately designed based on individual needs to optimize these effects. Therefore, we performed a narrative review of the literature, consulting the bibliographic databases MEDLINE and Google Scholar, to i) summarize the most recent scientific evidence on the effects of whole-body vibration and the molecular mechanisms proposed so far to provide a useful state of the art and ii) assess the potential of whole-body vibration as a form of passive training in place of or in association with exercise.

SARS-CoV-2 has caused a global pandemic and an unprecedented public health crisis, infecting more than 580 million people worldwide. Moreover, recent evidence has suggested the emergence of a new syndrome known as Long-COVID, a term used to describe a diverse set of physical and mental symptoms that persist after a diagnosed SARS-CoV-2 infection. Epidemiological data have identified myalgias, muscle and joint dysfunction, and bone fragility as common sequelae in patients with moderate and severe forms of this disease. Significant musculoskeletal dysfunction has also been detected in some healed patients, although knowledge about pathophysiological mechanisms of Long-COVID is still rather scarce. In this context, SARS-CoV-2 infection has been suggested to amplify the effects of aging on the musculoskeletal system by aggravating the osteosarcopenic state. Based on this evidence, our review focused on the muscle and bone tissue alterations induced by SARS-CoV-2 infection and Long-COVID, summarizing the current knowledge on the underlying biological mechanisms and highlighting the need for a multidisciplinary approach to predict the musculoskeletal targets and long-term consequences of COVID-19 disease., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Whole body vibration (WBV) is well known to exert beneficial effects on multiple tissues, improving synaptic transmission, muscle mass, bone quality, and reducing anxiety and depressive behavior. However, the underlying molecular mechanisms are not yet fully understood, and organs and tissues may respond differently to the vibratory stimulus depending on multiple factors. Therefore, we investigated the WBV effects on the brain and musculoskeletal tissue of 4-month-old young mice, evaluating synaptic plasticity by electrophysiological recordings and tissue organization by histology and histomorphometric analysis. Specifically, WBV protocols were characterized by the same vibration frequency (45 Hz), but different in vibration exposure time (five series of 3 min for the B protocol and three series of 2 min and 30 s for the C protocol) and recovery time between two vibration sessions (1 min for the B protocol and 2 min and 30 s for the C protocol). In addition, immunohistochemistry was conducted to evaluate the expression of fibronectin type III domain-containing protein 5 (FNDC5), as well as that of tissue-specific markers, such as brain-derived neurotrophic factor (BDNF) in brain, myostatin in muscle and collagen I (COL-1) in bone. Our results suggest that the WBV effects depend closely on the type of protocol used and support the hypothesis that different organs or tissues have different susceptibility to vibration. Further studies will be needed to deepen our knowledge of physiological adaptations to vibration and develop customized WBV protocols to improve and preserve cognitive and motor functions.

Musculoskeletal pain is a condition that characterises several diseases and represents a constantly growing issue with enormous socio-economic burdens, highlighting the importance of developing treatment algorithms appropriate to the patient's needs and effective management strategies. Indeed, the algic condition must be assessed and treated independently of the underlying pathological process since it has an extremely negative impact on the emotional and psychic aspects of the individual, leading to isolation and depression. A full understanding of the pathophysiological mechanisms involved in nociceptive stimulation and central sensitization is an important step in improving approaches to musculoskeletal pain. In this context, the bidirectional relationship between immune cells and neurons involved in nociception could represent a key point in the understanding of these mechanisms. Therefore, we provide an updated overview of the magnitude of the musculoskeletal pain problem, in terms of prevalence and costs, and summarise the role of the most important molecular players involved in the development and maintenance of pain. Finally, based on the pathophysiological mechanisms, we propose a model, called the "musculoskeletal pain cycle", which could be a useful tool to counteract resignation to the algic condition and provide a starting point for developing a treatment algorithm for the patient with musculoskeletal pain.

Scientific evidence has demonstrated the power of physical exercise in the prevention and treatment of numerous chronic and/or age-related diseases, such as musculoskeletal, metabolic, and cardiovascular disorders. In addition, regular exercise is known to play a key role in the context of neurodegenerative diseases, as it helps to reduce the risk of their onset and counteracts their progression. However, the underlying molecular mechanisms have not yet been fully elucidated. In this regard, neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glia cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), have been suggested as key mediators of brain health benefits, as they are involved in neurogenesis, neuronal survival, and synaptic plasticity. The production of these neurotrophic factors, known to be increased by physical exercise, is downregulated in neurodegenerative disorders, suggesting their fundamental importance in maintaining brain health. However, the mechanism by which physical exercise promotes the production of neurotrophins remains to be understood, posing limits on their use for the development of potential therapeutic strategies for the treatment of neurodegenerative diseases. In this literature review, we analyzed the most recent evidence regarding the relationship between physical exercise, neurotrophins, and brain health, providing an overview of their involvement in the onset and progression of neurodegeneration.

Bone loss is among the most frequent changes seen in astronauts during space missions. Although weightlessness is known to cause high bone resorption and a rapid decrease in bone minerals and calcium, the underlying mechanisms are not yet fully understood. In our work, we investigated the influence of random positioning machine (RPM) exposure on the mineralization process in the SAOS-2 cell line, in osteogenic and non-osteogenic conditions, by examining changes in their mineralizing capacity and in the expression of PTX3, a positive regulator of bone mineralization. We analyzed cell viability by MTS assay and the mineralization process after staining with Toluidine Blue and Alizarin Red, while PTX3 expression was investigated by immunocytochemistry and western blotting analysis. Our results showed that RPM exposure increased cells' viability and improved their mineralizing competence when not treated with osteogenic cocktail. In contrast, in osteogenic conditions, cells exposed to RPM showed a reduction in the presence of calcification-like structures, mineral deposits and PTX3 expression, suggesting that the effects of RPM exposure on mineralizing matrix deposition depend on the presence of osteogenic factors in the culture medium. Further studies will be needed to clarify the role of potential mineralization markers in the cellular response to the simulated biological effects of microgravity, paving the way for a new approach to treating osteoporosis in astronauts exposed to spaceflight.

Clusterin (CLU) is a secreted heterodimeric glycoprotein expressed in all organism fluids as well as in the intracellular matrix that plays key roles in several pathological processes. Its recent involvement in muscle degeneration of osteoporotic patients led to investigation of the role of CLU in bone metabolism, given the biochemical and biomechanical crosstalk of the bone-muscle unit. Quantitative real time-polymerase chain reaction (qRT-PCR) analysis of CLU expression was performed in both osteoblasts and Peripheral Blood Mononuclear Cells (PBMCs) from osteoporotic patients (OP) and healthy individuals (CTR). Furthermore, immunohistochemical analysis on femoral head tissues and enzyme-linked immunosorbent assay (ELISA) in plasma samples were performed to investigate CLU expression pattern. Finally, genotyping of CLU rs11136000 polymorphism has also been performed by qRT-PCR assays to explore a possible association with CLU expression levels. Data obtained showed a significantly increased expression level of secreted CLU isoform in PBMCs and osteoblasts from OP patients. Immunohistochemical analysis confirms the increased expression of CLU in OP patients, both in osteocytes and osteoblasts, while plasma analysis reveals a statistically significant decrease of CLU levels. Unfortunately, no functional association between CLU expression levels and the presence of CLU rs11136000 polymorphism in OP patients was found. These data suggest a potential role played by CLU as a potential biomarker for the diagnosis and prognosis of OP progression.

Several scientific evidence have shown that exposure to microgravity has a significant impact on the health of the musculoskeletal system by altering the expression of proteins and molecules involved in bone-muscle crosstalk, which is also observed in the research of microgravity effect simulation. Among these, the expression pattern of myostatin appears to play a key role in both load-free muscle damage and the progression of age-related musculoskeletal disorders, such as osteoporosis and sarcopenia. Based on this evidence, we here investigated the efficacy of treatment with anti-myostatin (anti-MSTN) antibodies on primary cultures of human satellite cells exposed to 72 h of random positioning machine (RPM). Cell cultures were obtained from muscle biopsies taken from a total of 30 patients (controls, osteoarthritic, and osteoporotic) during hip arthroplasty. The Pax7 expression by immunofluorescence was carried out for the characterization of satellite cells. We then performed morphological evaluation by light microscopy and immunocytochemical analysis to assess myostatin expression. Our results showed that prolonged RPM exposure not only caused satellite cell death, but also induced changes in myostatin expression levels with group-dependent variations. Surprisingly, we observed that the use of anti-MSTN antibodies induced a significant increase in cell survival after RPM exposure under all experimental conditions. Noteworthy, we found that the negative effect of RPM exposure was counteracted by treatment with anti-MSTN antibodies, which allowed the formation of numerous myotubes. Our results highlight the role of myostatin as a major effector of the cellular degeneration observed with RPM exposure, suggesting it as a potential therapeutic target to slow the muscle mass loss that occurs in the absence of loading., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cariati, Scimeca, Bonanni, Triolo, Naldi, Toro, Marini, Tancredi, Iundusi, Gasbarra and Tarantino.)

➤: Bone marrow edema (BME) is a nonspecific but relevant finding, usually indicating the presence of an underlying pathology., ➤: The gold standard technique for detecting BME is magnetic resonance imaging (MRI), as it allows for a correct diagnosis to be made, which is extremely important given the heterogeneity of BME-related diseases., ➤: Depending on the severity of painful symptomatology and the MRI evidence, different treatment strategies can be followed: physical modalities, pharmacological options, and surgical therapy., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G779)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Aerobic training is known to influence cognitive processes, such as memory and learning, both in animal models and in humans. Particularly, in vitro and in vivo studies have shown that aerobic exercise can increase neurogenesis in the dentate gyrus, improve hippocampal long-term potentiation (LTP), and reduce age-related decline in mnemonic function. However, the underlying mechanisms are not yet fully understood. Based on this evidence, the aim of our study was to verify whether the application of two aerobic training protocols, different in terms of speed and speed variation, could modulate synaptic plasticity in a young murine model. Therefore, we assessed the presence of any functional changes by extracellular recordings in vitro in mouse hippocampal slices and structural alterations by transmission electron microscopy (TEM). Our results showed that an aerobic training protocol, well designed in terms of speed and speed variation, significantly contributes to improving synaptic plasticity and hippocampal ultrastructure, optimizing its benefits in the brain. Future studies will aim to clarify the underlying biological mechanisms involved in the modulation of synaptic plasticity induced by aerobic training.

Bone marrow edema (BME) is defined as an area of low signal intensity on T1-weighted (T1W) MRI images and associated with intermediate or high signal intensity findings on T2-weighted (T2W) MRI images. BME represents a typical imaging finding that characterizes common stress-related bone injuries of professional and amateur athletes. The etiology of stress-related injuries is influenced by numerous factors, including the initiation of a new sports activity or changes in an existing training protocol. The clinical significance of BME remains unclear. However, a correlation between the imaging pattern of BME, the clinical history of the patient and the type of sports activity practiced is essential for correct diagnosis and adequate therapeutic treatment. It is also important to clarify whether there is a specific threshold beyond which exercise can adversely affect the bone remodeling process, as the clinical picture may degenerate into the presence of BME, pain and, in the most severe cases, bone loss. In our review, we summarize the current knowledge on the etiopathogenesis and treatment options for BME and highlight the main aspects that make it difficult to formulate a correct diagnosis and establish an adequate therapeutic treatment.

Cigarette smoking has a negative impact on the skeletal system, as it reduces bone mass and increases fracture risk through its direct or indirect effects on bone remodeling. Recent evidence demonstrates that smoking causes an imbalance in bone turnover, making bone vulnerable to osteoporosis and fragility fractures. Moreover, cigarette smoking is known to have deleterious effects on fracture healing, as a positive correlation between the daily number of cigarettes smoked and years of exposure has been shown, even though the underlying mechanisms are not fully understood. It is also well known that smoking causes several medical/surgical complications responsible for longer hospital stays and a consequent increase in the consumption of resources. Smoking cessation is, therefore, highly advisable to prevent the onset of bone metabolic disease. However, even with cessation, some of the consequences appear to continue for decades afterwards. Based on this evidence, the aim of our review was to evaluate the impact of smoking on the skeletal system, especially on bone fractures, and to identify the pathophysiological mechanisms responsible for the impairment of fracture healing. Since smoking is a major public health concern, understanding the association between cigarette smoking and the occurrence of bone disease is necessary in order to identify potential new targets for intervention.

Bone and muscle tissues influence each other through the integration of mechanical and biochemical signals, giving rise to bone-muscle crosstalk. They are also known to secrete osteokines, myokines, and cytokines into the circulation, influencing the biological and pathological activities in local and distant organs and cells. In this regard, even osteoporosis and sarcopenia, which were initially thought to be two independent diseases, have recently been defined under the term "osteosarcopenia", to indicate a synergistic condition of low bone mass with muscle atrophy and hypofunction. Undoubtedly, osteosarcopenia is a major public health concern, being associated with high rates of morbidity and mortality. The best current defence against osteosarcopenia is prevention based on a healthy lifestyle and regular exercise. The most appropriate type, intensity, duration, and frequency of exercise to positively influence osteosarcopenia are not yet known. However, combined programmes of progressive resistance exercises, weight-bearing impact exercises, and challenging balance/mobility activities currently appear to be the most effective in optimising musculoskeletal health and function. Based on this evidence, the aim of our review was to summarize the current knowledge about the role of exercise in bone-muscle crosstalk, highlighting how it may represent an effective alternative strategy to prevent and/or counteract the onset of osteosarcopenia.

Niemann-Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.

It has been proposed that a "common core" of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer's, Parkinson's, type II diabetes and Creutzfeldt-Jacob's Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca 2+ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific "common structure" of the toxic aggregate, and a "common mechanism" by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca 2+ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission.

Background: Osteosarcopenia is a recently identified condition caused by the coexistence of osteoporosis and sarcopenia that affects the frail elderly population, leading to an increased risk of falls and fractures. Given the recent socio-economic interest associated with osteosarcopenia, the aim of this meta-analysis is to provide an overview of the factors potentially involved in its pathogenesis, assessing its population type, prevalence, and associated variables., Methods: A comprehensive systematic search for relevant studies, published from 2015 to 2020, was performed by using PubMed, EMBASE, and Cochrane databases. We analysed the variables of age, vitamin D, handgrip, and T-score in four different groups: healthy, osteopenic-osteoporotic, sarcopenic, and osteosarcopenic., Results: A total of 6504 patients from 16 studies were included in the final meta-analysis. The analysis of the individual variables reveals a statistically significant correlation between the handgrip test data and T-score ( p < 0.001)., Conclusions: The correlation between T-score values and handgrip strength suggests a new potential parameter in the development of predictive models that could be used in clinical practice, highlighting its importance for the diagnosis of osteosarcopenia.

Whole body vibration plays a central role in many work categories and can represent a health risk to the musculoskeletal system and peripheral nervous system. However, studies in animal and human models have shown that vibratory training, experimentally and/or therapeutically induced, can exert beneficial effects on the whole body, as well as improve brain functioning and reduce cognitive decline related to the aging process. Since the effects of vibratory training depend on several factors, such as vibration frequency and vibration exposure time, in this work, we investigated whether the application of three different vibratory protocols could modulate synaptic and muscle plasticity in a middle-aged murine model, counteracting the onset of early symptoms linked to the aging process. To this end, we performed in vitro electrophysiological recordings of the field potential in the CA1 region of mouse hippocampal slices, as well as histomorphometric and ultrastructural analysis of muscle tissue by optic and transmission electron microscopy, respectively. Our results showed that protocols characterized by a low vibration frequency and/or a longer recovery time exert positive effects at both hippocampal and muscular level, and that these effects improve significantly by varying both parameters, with an action comparable with a dose-response effect. Thus, we suggested that vibratory training may be an effective strategy to counteract cognitive impairment, which is already present in the early stages of the aging process, and the onset of sarcopenia, which is closely related to a sedentary lifestyle. Future studies are needed to understand the underlying molecular mechanisms and to determine an optimal vibratory training protocol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cariati, Bonanni, Annino, Scimeca, Bonanno, D’Arcangelo and Tancredi.)

Pentraxin 3 (PTX3) is a glycoprotein belonging to the humoral arm of innate immunity that participates in the body's defence mechanisms against infectious diseases. It has recently been defined as a multifunctional protein, given its involvement in numerous physiological and pathological processes, as well as in the pathogenesis of age-related diseases such as osteoporosis. Based on this evidence, the aim of our study was to investigate the possible role of PTX3 in both the osteoblastic differentiation and calcification process: to this end, primary osteoblast cultures from control and osteoporotic patients were incubated with human recombinant PTX3 (hrPTX3) for 72 h. Standard osteinduction treatment, consisting of β-glycerophosphate, dexamethasone and ascorbic acid, was used as control. Our results showed that treatment with hrPTX3, as well as with the osteogenic cocktail, induced cell differentiation towards the osteoblastic lineage. We also observed that the treatment not only promoted an increase in cell proliferation, but also the formation of calcification-like structures, especially in primary cultures from osteoporotic patients. In conclusion, the results reported here suggest the involvement of PTX3 in osteogenic differentiation, highlighting its osteoinductive capacity, like the standard osteoinduction treatment. Therefore, this study opens new and exciting perspectives about the possible role of PTX3 as biomarker and therapeutic agent for osteoporosis., Competing Interests: The authors declare no conflict of interest.

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene ( 1-3 ) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1-3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4-) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

DNA methylation is one of the most studied epigenetic mechanisms that play a pivotal role in regulating gene expression. The epigenetic component is strongly involved in aging-bone diseases, such as osteoporosis and osteoarthritis. Both are complex multi-factorial late-onset disorders that represent a globally widespread health problem, highlighting a crucial point of investigations in many scientific studies. In recent years, new findings on the role of DNA methylation in the pathogenesis of aging-bone diseases have emerged. The aim of this systematic review is to update knowledge in the field of DNA methylation associated with osteoporosis and osteoarthritis, focusing on the specific tissues involved in both pathological conditions.

Salmon calcitonin is a good model for studying amyloid behavior and neurotoxicity. Its slow aggregation rate allows the purification of low molecular weight prefibrillar oligomers, which are the most toxic species. It has been proposed that these species may cause amyloid pore formation in neuronal membranes through contact with negatively charged sialic acid residues of the ganglioside GM1. In particular, it has been proposed that an electrostatic interaction may be responsible for the initial contact between prefibrillar oligomers and GM1 contained in lipid rafts. Based on this evidence, the aim of our work was to investigate whether the neurotoxic action induced by calcitonin prefibrillar oligomers could be counteracted by treatment with neuraminidase, an enzyme that removes sialic acid residues from gangliosides. Therefore, we studied cell viability in HT22 cell lines and evaluated the effects on synaptic transmission and long-term potentiation by in vitro extracellular recordings in mouse hippocampal slices. Our results showed that treatment with neuraminidase alters the surface charges of lipid rafts, preventing interaction between the calcitonin prefibrillar oligomers and GM1, and suggesting that the enzyme, depending on the concentration used, may have a partial or total protective action in terms of cell survival and modulation of synaptic transmission.

The Long Pentraxin 3 (PTX3) is a multifunctional glycoprotein released by peripheral blood leukocytes and myeloid dendritic cells in response to primary pro-inflammatory stimuli, that acts as a non-redundant component of the humoral arm of innate immunity. In addition to the primary role in the acute inflammatory response, PTX3 seems to be involved in other physiological and pathological processes. Indeed, PTX3 seems to play a pivotal role in the deposition and remodeling of bone matrix during the mineralization process, promoting osteoblasts differentiation and activity. Recently, PTX3 was seen to be involved in the ectopic calcifications' formation in breast cancer disease. In this regard, it has been observed that breast cancer tumors characterized by high expression of PTX3 and high amount of Breast Osteoblast Like Cells (BOLCs) showed several Hydroxyapatite (HA) microcalcifications, suggesting a likely role for PTX3 in differentiation and osteoblastic activity in both bone and extra-bone sites. Furthermore, given its involvement in bone metabolism, several studies agree with the definition of PTX3 as a molecule significantly involved in the pathogenesis of age-related bone diseases, such as osteoporosis, both in mice and humans. Recent results suggest that genetic and epigenetic mechanisms acting on PTX3 gene are also involved in the progression of these diseases. Based on these evidences, the aim of our systemic review was to offer an overview of the variety of biological processes in which PTX3 is involved, focusing on bone mineralization, both in a physiological and pathological context., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tarantino, Greggi, Cariati, Visconti, Gasparini, Cateni, Gasbarra, Botta, Salustri and Scimeca.)

In the past 40 years, scientific research has shown how Whole Body Vibration concept represents a strong stimulus for the whole organism. Low (<30 Hz), medium (30-80 Hz), and high (>80 Hz) frequency vibrations can have both positive and negative effects, depending on the oscillation type and duration of exposure to which the body is subjected. However, very little is known about the effects of vibratory training on the brain. In this regard, we verified whether three vibratory training protocols, differing in terms of vibration frequency and exposure time to vibration, could modulate synaptic plasticity in an experimental mouse model, by extracellular recordings in vitro in hippocampal slices of mice of 4 and 24 months old. Our results showed that vibratory training can modulate synaptic plasticity differently, depending on the protocol used, and that the best effects are related to the training protocol characterized by a low vibration frequency and a longer recovery time. Future studies will aim to understand the brain responses to various types of vibratory training and to explore the underlying mechanisms, also evaluating the presence of any structural and functional changes due to vibratory training.

Studies on the effectiveness of physical exercise to treat and/or prevent mental disorders are essential and particularly appropriate, given the rapid growth of the elderly population and the consequent increase in the prevalence of neurodegenerative diseases. The onset of neurodegenerative diseases is subtle, and progression is irreversible, as there is still no cure capable of stopping them permanently. Therefore, we should not underestimate these diseases and should immediately begin to combine the treatment with physical activity adapted to specific needs. Indeed, it is well known that physical activity has positive effects on mobility, autonomy, and functional capacity, improving not only cognitive functions, but also reducing the risk of developing dementia. Despite several studies in this field, to date there are no specific and effective protocols that promote physical exercise in people with dementia. Based on this evidence, the aim of the present work was to verify whether an adapted physical exercise regimen could promote the maintenance of psychomotor functions in elderly subjects and, therefore, delay the irreversible effects of combinations of dementia and other pathologies associated with aging. Our results clearly show that exercise is very effective in improving psychomotor functions and delaying the progress of neurodegenerative diseases in humans, since we observed that the subjects maintained their cognitive skills after 8 months of physical activity, moreover, two patients presented an amelioration. Based on the results obtained, we recommend that the motor practice, in any chosen form, be considered an integral part of prevention programs based on an active lifestyle in older people. Future studies will be necessary to establish how long lasting the benefits of a specific physical activity are and whether they are enough to delay cognitive decline.

Osteoporosis is a public health concern all over the world. As a chronic condition, it generally requires prolonged medical interventions to limit the risks of further bone loss, impaired skeletal integrity and the onset of fractures. This problem is further complicated by the fact that the abrupt cessation of some therapies may be associated with an increased risk of harm. It is in this context that the COVID-19 pandemic has caused an unprecedented disruption to the provision of healthcare worldwide, exceeding our worst expectations in terms of the number of lives lost and the rapidity at which consolidated economies and healthcare systems are being significantly damaged. In this review, we assessed the challenges and strategies used in the management of osteoporosis and fragility fracture care during the COVID-19 pandemic. We also examined the available evidence and provided clinical recommendations that will require reassessment as the worldwide response to COVID-19 evolves.

Background/aims: The study of the effects of simulated microgravity on primary cultures of human satellite cells represents a reliable model for identifying the biomolecular processes involved in mechanic load-related muscle mass loss. Therefore, this study aims to investigate the role of myostatin and Bone Morphogenetic Protein-2 in human satellite cells response to simulated microgravity condition., Methods: In order to identify the main molecules involved in the phenomena of degeneration/regeneration of muscle tissue related to the alteration of mechanic load, we performed a morphological and immunohistochemical study on 27 muscle biopsies taken from control, osteoporotic and osteoarthritic patients, underwent hip arthroplasty. For each patient, we set up primary satellite cell cultures subjected to normogravity and simulated microgravity (110h) regimens. Cellular functionality has been studied through a morphological evaluation performed by optical microscopy, and an ultrastructural evaluation carried out by transmission electron microscopy. Furthermore, we evaluated the expression of Bone Morphogenetic Protein-2 and myostatin through immunocytochemical reactions., Results: Our results showed that in the very early phases of simulated microgravity condition the satellite cells are more active than those subjected to the normogravity regime, as demonstrated by both the increase in the number of myotubes and the significant increase in the expression of Bone Morphogenetic Protein-2 in all experimental groups. However, with prolongated exposure to simulated microgravity regime (>72h), satellite cells and new formed myotubes underwent to cell death. It is important to note that, in early phases, simulated microgravity can stimulate the formation of new myotubes from satellite cells derived by osteoporotic patients. Furthermore, we observed that simulated microgravity can induce changes in myostatin expression levels by group-dependent variations., Conclusion: The results obtained allowed us to hypothesize a possible molecular mechanism of response to simulated microgravity, confirming the importance of Bone Morphogenetic Protein-2 and myostatin in the physio-pathogenesis of muscle tissue. In addition, these data can lay the foundation for new therapeutic approached in the prevention/cure of osteoporosis and sarcopenia., Competing Interests: The authors declare that they have no competing interests., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

The positive effects of physical activity on cognitive functions are widely known. Aerobic training is known to promote the expression of neurotrophins, thus inducing an increase in the development and survival of neurons, as well as enhancing synaptic plasticity. Based on this evidence, in the present study, we analyze the effects of two different types of aerobic training, progressive continuous (PC) and varying continuous (VC), on synaptic and muscular plasticity in heterozygous mice carrying the genetic mutation for Niemann-Pick type C disease. We also analyze the effects on synaptic plasticity by extracellular recordings in vitro in mouse hippocampal slices, while the morphological structure of muscle tissue was studied by transmission electron microscopy. Our results show a modulation of synaptic plasticity that varies according to the type of training protocol used, and only the VC protocol administered twice a week, has a significantly positive effect on long-term potentiation. On the contrary, ultrastructural analysis of muscle tissue shows an improvement in cellular conditions in all trained mice. These results confirm the beneficial effects of exercise on quality of life, supporting the hypothesis that physical activity could represent an alternative therapeutic strategy for patients with Niemann-Pick type C disease.

The effects of training on muscle structure are dependent on adaptive changes induced by different intensities of physical exercise. Evidence has shown that aerobic training is able to induce adaptive changes to muscle structure based on intensity. The aim of the present study was to investigate the effects of different methods of continuous aerobic training in mice using functional, morphological and biomolecular approaches. The continuous aerobic training methods used in the present study were uniform continuous training (UC), varying continuous training (VC) and progressive continuous training (PC). Mice were made to run 3 times a week for 12 weeks on a motorized RotaRod, following one of the three different training methods at different speeds. The results of the present study demonstrated that the various training methods had different effects on sarcomere length. Ultrastructural analysis demonstrated that UC training resulted in a shortening of sarcomere length, PC training resulted in an elongation of sarcomere length and VC training showed similar sarcomere length when compared with the control sedentary group. Additionally, succinate dehydrogenase complex flavoprotein subunit A levels in muscle tissue following VC training were higher compared with UC and PC training. Overall, the present study showed that varying exercise methods resulted in different types of muscle plasticity, and that the VC protocol resulted in increased coordination and strength endurance in the functional tests, in agreement with the ultrastructural and biochemical profile. These observations support the view that VC training may be more efficient in increasing performance and may thus form the basis of training regimens when an improvement of motor efficiency is required., (Copyright © 2020, Spandidos Publications.)

Background: Physical exercise can reduce the risk of developing chronic diseases and slow the onset of neurodegenerative diseases. Since it has not been assessed which kind of training protocol might positively modulate both synaptic and muscular plasticity in neurodegenerative diseases, we studied in a mouse model of Niemann Pick type C disease, a model of minimal Alzheimer's Disease, the effect of a short term protocol., Methods: We evaluated the effect of a short term, aerobic uniform exercise training on synaptic and muscle plasticity in three different mice groups: WT controls, NPC1+/- and NPC1-/- animals. The results were compared with those obtained in the sedentary respective groups. We analyzed the effects on synaptic plasticity by in vitro extracellular recordings in hippocampal mouse slices; moreover hippocampal and muscle tissue morphological structure have been investigated by transmission electron microscopy, to highlight any structural and functional changes due to training., Results: The results indicate a rescue of long-term potentiation in homozygous but not in heterozygous mice slices and an induction of neuronal plasticity, observed by morphological analysis, both in homozygous and in heterozygous trained mice., Conclusions: Hence this protocol is adequate to improve long term potentiation (LTP) impairment and counteract muscular deterioration in homozygous mice.

Amyloid protein misfolding results in a self-assembling aggregation process, characterized by the formation of typical aggregates. The attention is focused on pre-fibrillar oligomers (PFOs), formed in the early stages and supposed to be neurotoxic. PFOs structure may change due to their instability and different experimental protocols. Consequently, it is difficult to ascertain which aggregation species are actually neurotoxic. We used salmon Calcitonin (sCT) as an amyloid model whose slow aggregation rate allowed to prepare stable samples without photochemical cross-linking. Intracellular Ca 2+ rise plays a fundamental role in amyloid protein-induced neurodegerations. Two paradigms have been explored: (i) the "membrane permeabilization" due to the formation of amyloid pores or other types of membrane damage; (ii) "receptor-mediated" modulation of Ca 2+ channels. In the present paper, we tested the effects of native sCT PFOs- with respect to Monomer-enriched solutions in neurons characterized by an increasing degree of differentiation, in terms of -Ca 2+ -influx, cellular viability, -Long-Term Potentiation impairment, Post-Synaptic Densities and synaptophysin expression. Results indicated that PFOs-, but not Monomer-enriched solutions, induced abnormal -Ca 2+ -influx, which could only in part be ascribed to NMDAR activation. Thus, we propose an innovative neurotoxicity mechanism for amyloid proteins where "membrane permeabilization" and "receptor-mediated" paradigms coexist.