MAIN PROBLEM AND METHODS:This review aims to summarize the role of fat mass and obesity-associated protein (FTO) in neurological disorders and neuropathic pain (NP). RESULTS:Key findings suggest that in neurological disorders such as Alzheimer's disease, Parkinson's disease, and depression, FTO-regulated m6A modification plays a critical role in the hippocampus and striatum. FTO-mediated m6A modification is involved in the pathological processes of NP. These findings suggest that FTO may serve as a potential therapeutic target for neurological disorders and NP. Common mechanisms may include the regulation of downstream mTOR and BDNF/TrkB signaling pathways, as well as modulation of neuronal excitability and synaptic plasticity. However, research on the relationship between exercise and m6A modification remains in its early stages. Emerging evidence suggests that exercise reduces FTO expression and increases m6A levels in the hippocampus and hypothalamus, indicating that exercise may serve as an effective intervention for modulating epigenetic modifications in the central nervous system. CONCLUSIONS:This implies that exercise may serve as an effective intervention for modulating epigenetic modifications, potentially by downregulating the demethylase FTO, regulating m6A modification, enhancing synaptic plasticity, modulating neuronal excitability, and providing neuroprotection, thereby contributing to disease mitigation. We hypothesize that exercise may regulate neurological disorders and NP through FTO-mediated m6A modification, with FTO potentially serving as a biomarker.

Neuropathic pain (NP) is a chronic pain condition caused by nerve damage. Current NP treatments have limited efficacy and significant side effects. Emerging evidence demonstrates that N-methyl-d-aspartate receptors (NMDARs) play a key role in the development of NP, especially in their pre- and postsynaptic functions. This review provides an overview of the mechanistic roles of NMDARs in NP, focusing on their subunit structures and involvement in pain transmission. The interactions between NMDARs and other neurotransmitter receptors are further discussed, emphasizing NMDARs as a promising therapeutic target. Finally, we discuss the pharmacologic mechanisms of NMDARs relevant to pain management and nonpharmacologic interventions, which have not been covered in previous reviews. This review aims to advance future research on NMDAR-mediated mechanisms in NP and promote the development of targeted, low-side effect therapeutic strategies.

Swimming exercise may alleviate neuropathic pain (NP) in spared nerve injury (SNI) mice by regulating pain-related genes, such as miR-183 and Cacna2d2. However, the related upstream mechanism remains unclear. The demethylase fat-mass and obesity-associated protein (FTO) in the dorsal root ganglia (DRG) participates in NP through m6A modification. However, whether FTO-regulated m6A modification contributes to the analgesic effect of swimming remains unknown. This study aimed to investigate the influence of swimming on FTO expression in the DRG of SNI mice and clarify its role in regulating the m6A modification of miR-183 by inhibiting FTO expression. We established a male SNI mouse model, performed intrathecal injections of adeno-associated viruses to knock down or overexpress FTO, and manipulated the expression of FTO in male and female miR-183 knockout mice. In addition, we subjected the above models to six weeks of swimming training and analyzed the effects on pain behavior, m6A modification levels, and the expression of target gene transcription and protein levels. We observed that swimming exercise downregulated FTO mRNA and protein expressions in the injured L4-L6 DRGs of SNI mice, promoted the m6A modification of miR-183, and showed an association with the increased expression levels of miR-183. These outcomes further reduced the downstream target gene Cacna2d2 and the BDNF/TrkB signaling pathway, which alleviated mechanical and cold allodynia. This study suggested that swimming exercise alleviates NP, potentially by downregulating FTO and promoting m6A methylation of miR-183. FTO-regulated m6A modification plays a key role in the mechanism of exercise-induced analgesia.

Changes in DNA methylation and subsequent alterations in gene expression have opened a new direction in research related to the pathogenesis of peripheral neuropathic pain (PNP). This study aimed to reveal epigenetic perturbations underlying DNA methylation in the dorsal root ganglion (DRG) of rats with peripheral nerve injury in response to prior exercise and identify potential target genes involved. Male Sprague-Dawley rats were divided into three groups, namely, chronic constriction injury (CCI) of the sciatic nerve, CCI with prior 6-week swimming training (CCI_Ex), and sham operated (Sham). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used as the main observation indicators to evaluate behavioral changes associated with pain. In this study, 6-week swimming training before CCI prevented later chronic pain. In particular, CCI rats with prior exercise showed a significant increase in the MWT and TWL of the injured lateral hind paw compared with CCI rats without exercise on days 14, 21, and 28 after CCI. Whole-genome bisulfite sequencing from the injured lumbar (L4-L6) DRGs on the 28th day after surgery was detected. We also generated DNA methylation maps of the two comparisons (sham group vs. CCI and CCI groups vs. CCI_Ex group), and 396 overlapping differentially methylated region-related genes were found between the two comparisons. Moreover, we integrated RNA sequencing to understand the mechanism by which differential DNA methylation after CCI may influence gene expression. Finally, Ryr1 and Xirp2 were identified through association analysis of two omics and quantitative reverse-transcription polymerase chain reaction, respectively. The methylation levels of Ryr1 and Xirp2 were upregulated with a corresponding increase in their mRNA expression in the DRGs of CCI rats, whereas prior exercise downregulated Ryr1 methylation and restore its expression level. Functional enrichment analysis of both omics found that the calcium signaling pathway was significantly enriched. Therefore, the potential intervention targets (Ryr1 and Xirp2) in L4-L6 DRGs may be involved in prior exercise that attenuates PNP induced by CCI. This study provides crucial insights into the epigenetic regulation of PNP responses to prior exercise.

Knee osteoarthritis (KOA) is a prevalent degenerative joint disease characterized by pain, dysfunction, and stiffness, significantly impairing quality of life. While various interventions exist, aerobic exercise stands out as a safe and effective core treatment. This review synthesizes current evidence on the therapeutic benefits and underlying mechanisms of aerobic exercise for KOA. We recommend low-to-moderate intensity aerobic training (RPE 11–14) for KOA patients, performed 3–4 times per week for 30–60 min, for at least 6 weeks. Recommended modalities include gentle exercises like Wuqinxi, Baduanjin, and yoga, or water-based exercises and swimming, which can offer additional benefits for weight management. The therapeutic effects of aerobic exercise on KOA are multifaceted. Mechanistically, it modulates inflammatory responses by balancing pro- and anti-osteoclastogenic cytokines and inhibiting inflammatory signaling pathways, thereby alleviating pain and promoting cartilage repair. Additionally, aerobic exercise contributes to weight control, reducing knee joint load and improving cartilage health. It also provides appropriate mechanical loading to facilitate osteogenesis and preserves muscle mass, particularly in the lower extremities, mitigating muscle loss and reducing joint pressure. Despite these benefits, the precise exercise modalities, patterns, and intensities for different KOA grades remain to be fully defined and require further clinical validation. Future research should focus on quantifying exercise prescriptions to optimize anti-inflammatory effects, muscle preservation, and cartilage regeneration, as well as exploring the potential of combining aerobic exercise with other training types to enhance outcomes.

Neuropathic pain (NP) is a complex and prevalent chronic pain condition that affects millions of individuals worldwide. Previous studies have shown that prior exercise protects against NP caused by nerve injury. However, the underlying mechanisms of this protective effect remain to be uncovered. Therefore, the purpose of this study is to investigate how prior exercise affects protein expression in NP model rats and thus gain comprehensive insights into the molecular mechanisms involved. To achieve this objective, 6-week-old male Sprague-Dawley rats were randomly assigned into three groups, named as chronic constriction injury (CCI) of the sciatic nerve, CCI with prior 6-week swimming training (CCI_Ex), and sham operated (Sham). The CCI_Ex group underwent 6 weeks of swimming training before CCI surgery, while the CCI and sham groups had no intervention. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used as the main observation indicators to evaluate the behavioral changes associated with pain. Tissues from the spinal dorsal horn of the rats in the three groups were collected at 4 weeks after operation. LC-MS/MS proteomic analysis based on the label-free approach was used to detect protein profiles, and volcano plots, Venn diagrams, and clustering heatmaps were used to identify differentially expressed proteins (DEPs). Gene Ontology (GO) annotations, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction networks were employed to explore the biological importance of DEPs. At 14, 21, and 28 days following CCI, CCI rats with prior exercise showed a significant increase in the MWT and TWL of the injured lateral hind paw compared with those without exercise. A total of 122 proteins with significant changes in abundance were detected after CCI surgery, and 55 proteins were detected in the comparison between the CCI_Ex and CCI groups. GO and KEGG enrichment analysis revealed that oxygen transport capacity and the complement and coagulation cascades may be the critical mechanism by which prior exercise protects against NP. Serpina1, DHX9, and Alb are the key proteins in this process and warrant further attention, as confirmed by the results of Western blot analysis. In conclusion, this study provides new evidence that active physical activity can accelerate the relief of hyperalgesia after NP. Proteomic analyses revealed the potential target proteins and pathways for this process, offering valuable data resources and new insights into the pathogenesis and therapeutic targets of NP.

Neuropathic pain (NP) resulting from a lesion or disease of the somatosensory system can lead to loss of function and reduced life quality. Neuroinflammation plays a vital role in the development and maintenance of NP. Exercise as an economical, effective, and nonpharmacological treatment, recommended by clinical practice guidelines, has been proven to alleviate chronic NP. Previous studies have shown that exercise decreases NP by modifying inflammation; however, the exact mechanisms of exercise-mediated NP are unclear. Therefore, from the perspective of neuroinflammation, this review mainly discussed the effects of exercise on inflammatory cytokines in different parts of NP conduction pathways, such as the brain, spinal cord, dorsal root ganglion, sciatic nerve, and blood in rat/mice models. Results suggested that exercise training could modulate neuroinflammation, inhibit astrocyte glial cell proliferation and microglial activation, alter the macrophage phenotype, reduce the expression of proinflammatory cytokines, increase anti-inflammatory cytokine levels, and positively modulate the state of the immune system, thereby relieving NP.

OBJECTIVE: To examine the associations between (1) various types of physical activity and the risk of back pain incidence, and (2) the influence of substituting sedentary behaviors with physical activities on back pain incidence. DESIGN: A prospective cohort study. METHODS: We analyzed UK Biobank data collected from 365 307 participants who were free of back pain at baseline. The exposures were total, light, moderate, and vigorous physical activity, and sedentary behaviors. The outcome was back pain incidence. The main statistical models were the Cox proportional hazard model and the isotemporal substitution model. RESULTS: In the follow-up time (median, 12.97 years; interquartile range, 12.10-13.71), 25 189 individuals developed back pain. The associations between all types of physical activity and incident back pain were significantly nonlinear ( P <.001) among the general population and other subgroups. High physical activity was associated with a decreased risk of back pain compared with no physical activity. The lowest risk occurred in the 1801-to-2400 MET-min/week (metabolic-equivalent minutes per week) subgroup of total physical activity (hazard ratio [HR] = 0.64; 95% CI: 0.59, 0.69), approximately consisting of 1200, 600, and 600 MET-min/week of light, moderate, and vigorous physical activity, respectively. Extremely high vigorous physical activity was related to high risk, specifically in males (HR = 1.13; 95% CI: 1.02, 1.25). Replacing 1 hour/day of sedentary behaviors with an equal time of physical activity reduced the risk of incident back pain by 2% to 8% ( P <.05). CONCLUSION: Physical activity was related to a reduced risk of back pain incidence (except over high vigorous physical activity). Substituting sedentary behaviors with physical activities reduced the risk of future back pain. J Orthop Sports Phys Ther 2024;54(7):468-476. Epub 30 April 2024.

The benefits of exercise on neuropathic pain (NP) have been demonstrated in numerous studies. In recent studies, inflammation, neurotrophins, neurotransmitters, and endogenous opioids are considered as the main mechanisms. However, the role of exercise in alleviating NP remains unclear. Neuroglia, widely distributed in both the central and peripheral nervous systems, perform functions such as support, repair, immune response, and maintenance of normal neuronal activity. A large number of studies have shown that neuroglia play an important role in the occurrence and development of NP, and exercise can alleviate NP by regulating neuroglia. This article reviewed the involvement of neuroglia in the development of NP and their role in the exercise treatment of NP, intending to provide a theoretical basis for the exercise treatment strategy of NP.

Neuropathic pain (NP) is a chronic pain caused by injury or disease of the somatosensory nervous system, or it can be directly caused by disease. It often presents with clinical features like spontaneous pain, hyperalgesia, and dysesthesia. At present, voltage-gated calcium ion channels (VGCCs) are known to be closely related to the development of NP, especially the α2δ subunit. The α2δ subunit is a regulatory subunit of VGCCs. It exists mainly in the brain and peripheral nervous system, especially in nerve cells, and it plays a crucial part in regulating presynaptic and postsynaptic functions. Furthermore, the α2δ subunit influences neuronal excitation and pain signaling by promoting its expression and localization through binding to VGCC-related subunits. The α2δ subunit is widely used in the management of NP as a target of antiepileptic drugs gabapentin and pregabalin. Although drug therapy is one of the treatments for NP, its clinical application is limited due to the adverse reactions caused by drug therapy. Therefore, further research on the therapeutic target α2δ subunit is needed, and attempts are made to obtain an effective treatment for relieving NP without side effects. This review describes the current associated knowledge on the function of the α2δ subunit in perceiving and modulating NP.

BACKGROUND:The effect of physical therapy on pain and disability alleviation in patients with chronic low back pain (cLBP) has been demonstrated, but the risk factors for treatment failure remain unknown. AIM:To explore the associations of baseline demographic and clinical characteristics with treatment failure after physical therapy intervention for cLBP. DESIGN:A secondary analysis of a single-blind randomized clinical trial. SETTING:A rehabilitation hospital. POPULATION:A total of 98 patients with cLBP completed the 12-month measurement. METHODS:Patients were randomly grouped into 3-month therapeutic aquatic exercise or physical therapy modalities. The primary outcome was treatment failure, which was defined as a decrease in the numeric rating scale to less than 2.0 points at 12-month follow-up. Associations between baseline demographic and clinical characteristics with risk of treatment failure were assessed by logistic regressions. RESULTS:The pain intensity in the failure cases was alleviated after 3-month intervention but continuously increased at 6- and 12-month follow-up (P<0.05). Old age was significantly associated with an increased risk of treatment failure (adjusted OR 3.26, 95% CI 1.11-9.60). Compared with those receiving physical therapy modalities, the patients receiving therapeutic aquatic exercise had less risk of treatment failure (adjusted OR 0.19, 95% CI 0.08-0.47), and age (P=0.022) was a modifier for this association. CONCLUSIONS:Compared with younger ones, older patients with cLBP had a higher risk of treatment failure after physical therapy and gained a stronger benefit of long-term pain alleviation from therapeutic aquatic exercise. CLINICAL REHABILITATION IMPACT:Therapeutic aquatic exercise is an effective therapy for cLBP and more helpful for preventing treatment failure than physical therapy modalities, especially for older patients.

Low back pain (LBP) is a common symptom that can occur in all ages. It is the first common cause of disability globally and is associated with over 60 million disability-adjusted life-years in a single year. Motor control exercise (MCE) has obtained increasing attention in treating LBP. However, the findings from distinct meta-analyses differed and some even reached controversial conclusions. More importantly, how MCE improves LBP-related symptoms remains unclear. The primary aim of this study is to describe the possible improvement mechanisms of MCE on LBP from brain, biochemistry, inflammatory, and neuromuscular aspects. The secondary aim is to further conclude its effectiveness and clinical application. Further understanding of mechanisms and effectiveness could be instructive for future LBP treatments and provide more information for clinicians when making prescriptions. MCE is effective in alleviating pain and disability among patients with acute and chronic LBP. Notably, the evidence for acute LBP is relatively low-quality and limited. MCE might be more effective for patients with specific LBP characteristics, especially those with pre-diagnosis of impaired transversus abdominis recruitment, intermediate pain intensity, and longer MCE training duration. MCE could remap brain representation and reverse negative brain alternation, induce exercise-induced hypoalgesia, mediate anti-inflammatory response, retain normal activation, and improve morphological deficits.

Inflammatory pain refers to the increased sensitivity of perception and emotional response to noxious stimuli, that arises from an inflammatory reaction associated with tissue damage (Layne-Stuart and Carpenter, 2022). Under normal conditions, acute inflammation is a protective response by the body to tissue damage or infection, potentially leading to the perception of pain while damaged tissues are being cleared and repaired (Muley et al., 2016). Inflammatory pain can serve as a reminder of a recent injury to prevent re-injury and thereby achieve quick recovery. In general, inflammation management effectively relieves inflammatory pain due to the reduced stimulation of nerves following the resolution of inflammation. However, chronic inflammation can lead to adverse pain because inflammatory mediators act on pain-sensitive nerve endings by decreasing the thresholds of neuronal excitability, and increasing the sensitivity of firing rates, thereby causing peripheral and central sensitization (Prescott and Ratté , 2017). Under these sensitized conditions, pain perception can be abnormal, such as allodynia (perceiving innocuous stimuli as painful) and hyperalgesia (amplifying the intensity and duration of pain caused by noxious stimuli) (Laverdure-Dupont et al., 2009). In clinics, chronic pain is normally a complex of inflammatory and neuropathic components.Inflammatory mediators can result in neuronal damage, which triggers an inflammatory reaction.

Objective:To conduct a bibliometric analysis of trends and frontiers on exercise-based non-pharmacological treatments for movement disorders published between 2010 and 2021.Methods:The Web of Science (WOS) Core Collection database was searched for articles published between 2010 and 2021. The CiteSpace software was used for in-depth analysis of the countries, institutions, journals, and collaboration networks among authors and their types of articles, developmental directions, references, and hot keywords of published articles.Results:A total of 2,626 published articles were retrieved by search formula and included in the analysis. The number of publications fluctuated during this period, with 96 countries, 3,058 institutions, and 886 academic journals having published articles in this area, with subject classifications that focused on Clinical Neurology and Neurosciences. The United States has maintained its dominant and most influential position in exercise-based non-pharmacological research on movement disorders. Among research institutions and journals, the League of European Research Universities and Movement Disorders journals published the highest number of academic articles. In the last five years, the hot research topics by burst keyword analysis, are focused on treatments, research advances, and clinical treatments.Conclusion:Research on exercise-based non-pharmacological treatments for movement disorders is generally on the rise from 2010 to 2021. The bibliometric analysis of this area will help provide potential collaborations among researchers, frontiers, and directions for development.

Exercise can help inhibition of neuropathic pain (NP), but the related mechanism remains being explored. In this research, we performed the effect of swimming exercise on the chronic constriction injury (CCI) rats. Compared with CCI group, the mechanical withdrawal threshold of rats in the CCI-Swim group significantly increased on the 21st and 28th day after CCI surgery. Second-generation RNA-sequencing technology was employed to investigate the transcriptomes of spinal dorsal horns in the Sham, CCI, and CCI-Swim groups. On the 28th day post-operation, 306 intersecting long non-coding RNAs (lncRNAs) and 173 intersecting mRNAs were observed between the CCI vs Sham group and CCI-Swim vs CCI groups. Then, the biological functions of lncRNAs and mRNAs in the spinal dorsal horn of CCI rats were then analyzed. Taking the results together, this study could provide a novel perspective for the treatment for NP.

Neuropathic pain (NP) results from a lesion or disease of the nervous system and accompanied by chronic pain, leading a serious public health issue and economic burden. In terms of the NP mechanisms remaining poorly understood, circular RNAs (circRNAs), owing to their high stability and evolutionary conservation, are expected to be used as potential therapeutic targets or diagnostic biomarkers. In this review, we concisely discuss the characteristics and biological functions of circRNAs. As emerging evidence we reviewed, deregulation of circRNAs (e.g., circ-Filip1l, circHIPK3, ciRS-7, circRNA.2837, circ-Ankib1 and circAnks1a) were involved in NP development. It suggested that specific circRNAs modulated through sponging their target miRNAs and thus regulated the homologous downstream mRNAs and proteins in neuropathic pain. These findings provide a theoretical basis for circRNAs use as biomarkers and therapeutic targets in neuropathic pain.

Osteoporosis (OP) is a disease that weakens bones and has a high morbidity rate worldwide, which is prevalent among the elderly, particularly, women of postmenopausal age. The dynamic balance between bone formation and resorption is necessary for normal bone metabolism. Many factors, including aging, estrogen deficiency, and prolonged immobilization, disrupt normal apoptosis, autophagy, and inflammation, leading to abnormal activation of osteoclasts, which gradually overwhelm bone formation by bone resorption. Moderate exercise as an effective non-drug treatment helps increase bone formation and helps relieve OP. The possible mechanisms are that exercise affects apoptosis and autophagy through the release of exercise-stimulated myohormone and the secretion of anti-inflammatory cytokines via mechanical force. In addition, exercise may also have an impact on the epigenetic processes involved in bone metabolism. Mechanical stimulation promotes bone marrow mesenchymal stem cells (BMSCs) to osteogenic differentiation by altering the expression of non-coding RNAs. Besides, by reducing DNA methylation, the mechanical stimulus can also alter the epigenetic status of osteogenic genes and show associated increased expression. In this review, we reviewed the possible pathological mechanisms of OP and summarized the effects of exercise on bone metabolism, and the mechanisms by which exercise alleviates the progression of OP, to provide a reference for the prevention and treatment of OP.

Diabetic neuropathic pain (DNP) is a common disease that affects the daily lives of diabetic patients, and its incidence rate is very high worldwide. At present, drug and exercise therapies are common treatments for DNP. Drug therapy has various side effects. In recent years, exercise therapy has received frequent research and increasing attention by many researchers. Currently, the treatment of DNP is generally symptomatic. We can better select the appropriate exercise prescription for DNP only by clarifying the exercise mechanism for its therapy. The unique pathological mechanism of DNP is still unclear and may be related to the pathological mechanism of diabetic neuropathy. In this study, the mechanisms of exercise therapy for DNP were reviewed to understand better the role of exercise therapy in treating DNP.

Finding new biomarkers and molecular targets to guide OA treatment remains a significant challenge. One of the most frequent forms of RNA methylation, N6-methyladenosine (m6A), can affect gene expression and RNA transcription, processing, translation, and metabolism. Osteoarthritis (OA) can cause disability and pain degenerative disease, reduce the quality of life of the elderly, and increase the social and economic burden. Changes in m6A levels are crucial in OA progress. In this review, the discussion will concentrate on the role that m6A plays in OA occurrence and progression. The m6A involved in the OA process mainly includes METTL3 and FTO. Current studies on m6A and OA primarily focus on four signaling pathways, namely, NF-κB, LNCRNAs, ATG7, and Bcl2. m6A participates in these signaling pathways and affects cellular inflammation, apoptosis, senescence, and autophagy, thus controlling the OA process. The modification of m6A affects so many signaling pathways. For the treatment of OA, it may represent a viable new therapeutic target.

Background Diabetic peripheral neuropathic pain (DPNP) is a usual complication of diabetes with a high incidence and mortality. Many diabetes-related studies have been published in various journals. However, bibliometrics and visual analyses in the domain of DPNP research are still lacking. The study aimed to offer a visual method to observe the systematic overview of global research in this field from 2011 to 2021. Methods The publications from the Science Citation Index Expanded in Web of Science (WOS) in the past 11 years (from 2011 to 2021) were collected and sorted out, and those related to DPNP were extracted and analyzed. The article language was limited in English. Then, CiteSpace V was used for the bibliometric analysis of the extracted literature. Results A total of 1,422 articles met the inclusion criteria. A continuous but unstable growth in the amounts of papers published on DPNP was observed over the last 11 years. The subject sort of the 1,422 papers mainly concentrates on Endocrinology Metabolism, Clinical neurology and Neurosciences from the WOS. According to the research contribution in the field of DPNP, the United States occupies a leading position, with the highest amounts of publications, citations, open access, and the H- index. Conclusion This study provides a visual analysis method for the trend of DPNP, and offers some hidden serviceable information that may define new directions for future research.