Harnessing immunomodulation to combat sarcopenia: current insights and possible approaches.

Sarcopenia is a complex age-associated syndrome of progressive loss of muscle mass and strength. Although this condition is influenced by many factors, age-related changes in immune function including immune cell dynamics, and chronic inflammation contribute to its progression. The complex interplay between the immune system, gut-muscle axis, and autophagy further underscores their important roles in sarcopenia pathogenesis. Immunomodulation has emerged as a promising strategy to counteract sarcopenia. Traditional management approaches to treat sarcopenia including physical exercise and nutritional supplementation, and the emerging technologies of biophysical stimulation demonstrated the importance of immunomodulation and regulation of macrophages and T cells and reduction of chronic inflammation. Treatments to alleviate low-grade inflammation in older adults by modulating gut microbial composition and diversity further combat sarcopenia. Furthermore, some pharmacological interventions, nano-medicine, and cell therapies targeting muscle, gut microbiota, or autophagy present additional avenues for immunomodulation in sarcopenia. This narrative review explores the immunological underpinnings of sarcopenia, elucidating the relationship between the immune system and muscle during ageing. Additionally, the review discusses new areas such as the gut-muscle axis and autophagy, which bridge immune system function and muscle health. Insights into current and potential approaches for sarcopenia management through modulation of the immune system are provided, along with suggestions for future research directions and therapeutic strategies. We aim to guide further investigation into clinical immunological biomarkers and identify indicators for sarcopenia diagnosis and potential treatment targets to combat this condition. We also aim to draw attention to the importance of considering immunomodulation in the clinical management of sarcopenia.

Sarcopenia and Ageing.

Musculoskeletal ageing is a major health challenge as muscles and bones constitute around 55-60% of body weight. Ageing muscles will result in sarcopenia that is characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes. In recent years, a few consensus panels provide new definitions for sarcopenia. It was officially recognized as a disease in 2016 with an ICD-10-CM disease code, M62.84, in the International Classification of Diseases (ICD). With the new definitions, there are many studies emerging to investigate the pathogenesis of sarcopenia, exploring new interventions to treat sarcopenia and evaluating the efficacy of combination treatments for sarcopenia. The scope of this chapter is to summarize and appraise the evidence in terms of (1) clinical signs, symptoms, screening, and diagnosis, (2) pathogenesis of sarcopenia with emphasis on mitochondrial dysfunction, intramuscular fat infiltration and neuromuscular junction deterioration, and (3) current treatments with regard to physical exercises and nutritional supplement.

Comparative Analysis of Mitochondria Surrounding the Intercalated Discs in Heart Diseases-An Ultrastructural Pilot Study.

BACKGROUND: Mitochondria play a crucial role in adapting to fluctuating energy demands, particularly in various heart diseases. This study investigates mitochondrial morphology near intercalated discs in left ventricular (LV) heart tissues, comparing samples from patients with sinus rhythm (SR), atrial fibrillation (AF), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). METHODS: Transmission electron microscopy was used to analyze mitochondria within 0-3.5 µm and 3.5-7 µm of intercalated discs in 9 SR, 10 AF, 9 DCM, and 8 ICM patient samples. Parameters included mean size in µm2 and elongation, count, percental mitochondrial area in the measuring frame, and a conglomeration score. RESULTS: AF patients exhibited higher counts of small mitochondria in the LV myocardium, resembling SR. DCM and ICM groups had fewer, larger, and often hydropic mitochondria. Accumulation rates and percental mitochondrial area were similar across groups. Significant positive correlations existed between other defects/size and hydropic mitochondria and between count/area and conglomeration score, while negative correlations between count and size/other defects and between hydropic mitochondria and count could be seen as well. CONCLUSION: Mitochondrial parameters in the LV myocardium of AF patients were similar to those of SR patients, while DCM and ICM displayed distinct changes, including a decrease in number, an increase in size, and compromised mitochondrial morphology. Further research is needed to fully elucidate the pathophysiological role of mitochondrial morphology in different heart diseases, providing deeper insights into potential therapeutic targets and interventions.

The imminent risk of a fracture-existing worldwide data: a systematic review and meta-analysis.

The overall incidence of imminent fracture after a prior fragility fracture was 7.58% in the first year and 11.58% in the first 2 years. Approximately half of re-fractures occurred in the first 2 years after a fragility fracture. Older patients that have suffered from a fragility fracture should be treated promptly, with immediate care and a secondary fracture prevention to prevent the high imminent risk of a fracture. INTRODUCTION: Imminent fractures refer to the fractures that occur within 2 years of an initial fracture. It is well known that the risk of a subsequent fracture is not constant with time and occurs shortly after the initial one. This systematic review and meta-analysis aimed to present the existing data on imminent fracture worldwide. METHODS: Literature search was conducted in Pubmed, Embase, and Web of Science databases until 26 October 2021 for studies reporting the incidence of imminent osteoporotic fractures among people aged 50 years or older. The overall incidence of imminent fracture was pooled and subgroup analyses of index fracture sites and regions on incidence of imminent fracture were performed, with the 95% confidence interval (CI) being calculated. Percentage of imminent fracture occurring in follow-up period was calculated and pooled by meta-analysis. Hazard ratio (HR) was used to estimate the gender differences on the imminent risk of fracture. RESULTS: A total of 1446 articles were identified. Nineteen observational studies were eligible for our systematic review, in which 18 were used for quantitative analysis. Pooled overall incidence of imminent fracture in the first year after an osteoporotic fracture was 7.58% (95% CI 5.84 to 9.31%) and cumulative incidence in the first 2 years was 11.58% (95% CI 8.94 to 14.21%). Subgroup analysis showed that in the first 2 years, the pooled incidence in Asia was 7.30% (95% CI 3.42 to 11.18%), whilst incidence in Europe/North America was 13.17% (95% CI 10.14 to 16.20%). In included studies with follow-up period of more than 5 years, pooled imminent fracture percentage in the first 2 years was 47.24% (95% CI 26.18 to 68.30%). Hazard ratio (HR) on gender showed that women had an overall slight increase in risk of imminent fractures (HR 1.18, 95% CI 1.11 to 1.25). CONCLUSION: The incidence of imminent fracture is high globally at 11.58%. Approximately half of all refractures occur in the first 2 years after an index fragility fracture. Older patients that have suffered from a fragility fracture should be treated promptly. Also, immediate care and secondary fracture prevention are necessary to prevent the high imminent risk of a fracture, especially within the first 2 years.

Coapplication of Magnesium Supplementation and Vibration Modulate Macrophage Polarization to Attenuate Sarcopenic Muscle Atrophy through PI3K/Akt/mTOR Signaling Pathway.

Sarcopenia is an age-related geriatric syndrome characterized by the gradual loss of muscle mass and function. Low-magnitude high-frequency vibration (LMHFV) was shown to be beneficial to structural and functional outcomes of skeletal muscles, while magnesium (Mg) is a cofactor associated with better indices of skeletal muscle mass and strength. We hypothesized that LMHFV, Mg and their combinations could suppress inflammation and sarcopenic atrophy, promote myogenesis via PI3k/Akt/mTOR pathway in senescence-accelerated mouse P8 (SAMP8) mice and C2C12 myoblasts. Results showed that Mg treatment and LMHFV could significantly decrease inflammatory expression (C/EBPα and LYVE1) and modulate a CD206-positive M2 macrophage population at month four. Mg treatment also showed significant inhibitory effects on FOXO3, MuRF1 and MAFbx mRNA expression. Coapplication showed a synergistic effect on suppression of type I fiber atrophy, with significantly higher IGF-1, MyoD, MyoG mRNA (p < 0.05) and pAkt protein expression (p < 0.0001) during sarcopenia. In vitro inhibition of PI3K/Akt and mTOR abolished the enhancement effects on myotube formation and inhibited MRF mRNA and p85, Akt, pAkt and mTOR protein expressions. The present study demonstrated that the PI3K/Akt/mTOR pathway is the predominant regulatory mechanism through which LMHFV and Mg enhanced muscle regeneration and suppressed atrogene upregulation.

Can we enhance osteoporotic metaphyseal fracture healing through enhancing ultrastructural and functional changes of osteocytes in cortical bone with low-magnitude high-frequency vibration?

Fragility fractures are related to the loss of bone integrity and deteriorated morphology of osteocytes. Our previous studies have reported that low-magnitude high-frequency vibration (LMHFV) promoted osteoporotic fracture healing. As osteocytes are known for mechanosensing and initiating bone repair, we hypothesized that LMHFV could enhance osteoporotic fracture healing through enhancing morphological changes in the osteocyte lacuna-canalicular network (LCN) and mineralization. A metaphyseal fracture model was established in female Sprague-Dawley rats to investigate changes in osteocytes and healing outcomes from early to late phase post-fracture. Our results showed that the LCN exhibited an exuberant outgrowth of canaliculi in the osteoporotic fractured bone at day 14 after LMHFV. LMHFV upregulated the E11, dentin matrix protein 1 (DMP1), and fibroblast growth factor 23 (FGF23), but downregulated sclerostin (Sost) in osteocytes. Moreover, LMHFV promoted mineralization with significant enhancements of Ca/P ratio, mineral apposition rate (MAR), mineralizing surface (MS/BS), and bone mineral density (BMD) in the osteoporotic group. Consistently, better healing was confirmed by microarchitecture and mechanical properties, whereas the enhancement in osteoporotic group was comparable or even greater than the normal group. This is the first report to reveal the enhancement effect of LMHFV on the osteocytes' morphology and functions in osteoporotic fracture healing.

Acute Inflammatory Response in Osteoporotic Fracture Healing Augmented with Mechanical Stimulation is Regulated In Vivo through the p38-MAPK Pathway.

Low-magnitude high-frequency vibration (LMHFV) has previously been reported to modulate the acute inflammatory response of ovariectomy-induced osteoporotic fracture healing. However, the underlying mechanisms are not clear. In the present study, we investigated the effect of LMHFV on the inflammatory response and the role of the p38 MAPK mechanical signaling pathway in macrophages during the healing process. A closed femoral fracture SD rat model was used. In vivo results showed that LMHFV enhanced activation of the p38 MAPK pathway at the fracture site. The acute inflammatory response, expression of inflammatory cytokines, and callus formation were suppressed in vivo by p38 MAPK inhibition. However, LMHFV did not show direct in vitro enhancement effects on the polarization of RAW264.7 macrophage from the M1 to M2 phenotype, but instead promoted macrophage enlargement and transformation to dendritic monocytes. The present study demonstrated that p38 MAPK modulated the enhancement effects of mechanical stimulation in vivo only. LMHFV may not have exerted its enhancement effects directly on macrophage, but the exact mechanism may have taken a different pathway that requires further investigation in the various subsets of immune cells.

The Predictive Value of Sarcopenia and Falls for 2-Year Major Osteoporotic Fractures in Community-Dwelling Older Adults.

To evaluate the associations of sarcopenia and previous falls with 2-year major osteoporotic fractures (MOFs) in community-dwelling older adults. Four thousand Chinese men and women ≥ 65 years recruited from Hong Kong communities were prospectively followed up. Measures of muscle mass, grip strength, gait speed and falls in the previous year were recorded at baseline, the 2nd year and the 4th year visit for each subject. The associations of fall history, sarcopenia and its components with 2-year MOFs were evaluated using generalized linear mixed models. Poor grip strength and poor gait speed were significantly associated with a higher 2-year MOFs risk, with an adjusted OR (95% CI) per one SD decrease of 1.48 (1.17, 1.87) and 1.17 (1.00, 1.36), respectively. Falls in the previous year was a significant predictor for 2-year MOFs risk, with an adjusted OR (95% CI) per one added fall of 1.85 (1.40, 2.44) in men and 1.26 (1.01, 1.58) in women. The adjusted OR (95% CI) of height adjusted appendicular lean muscle mass (ALM/height2) per one SD decrease and sarcopenia for 2-year MOFs risk were 1.34 (0.87, 2.06) and 1.72 (0.92, 3.21) in men, and were 0.73 (0.57, 0.93) and 0.76 (0.39, 1.47) in women, respectively (P for interaction by gender = 0.012 and 0.017, respectively). Poor sarcopenia-related physical performance and falls in the previous year were significant predictors for 2-year MOFs in community-dwelling older adults. The predictive value of ALM by DXA for near-term fracture risk is limited and different across genders.

Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole.

Aromatase inhibitors (AIs) have been used as adjuvant therapeutic agents for breast cancer. Their adverse side effect on blood lipid is well documented. Some natural compounds have been shown to be potential AIs. In the present study, we compared the efficacy of the flavonoid luteolin to the clinically approved AI letrozole (Femara; Novartis Pharmaceuticals, East Hanover, NJ) in a cell and a mouse model. In the in vitro experimental results for aromatase inhibition, the Ki values of luteolin and letrozole were estimated to be 2.44 µM and 0.41 nM, respectively. Both letrozole and luteolin appeared to be competitive inhibitors. Subsequently, an animal model was used for the comparison. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. Luteolin was given by mouth at 5, 20, and 50 mg/kg, whereas letrozole was administered by intravenous injection. Similar to letrozole, luteolin administration reduced plasma estrogen concentrations and suppressed the xenograft proliferation. The regulation of cell cycle and apoptotic proteins-such as a decrease in the expression of Bcl-xL, cyclin-A/D1/E, CDK2/4, and increase in that of Bax-was about the same in both treatments. The most significant disparity was on blood lipids. In contrast to letrozole, luteolin increased fasting plasma high-density lipoprotein concentrations and produced a desirable blood lipid profile. These results suggested that the flavonoid could be a coadjuvant therapeutic agent without impairing the action of AIs.

Callus formation is related to the expression ratios of estrogen receptors-alpha and -beta in ovariectomy-induced osteoporotic fracture healing.

INTRODUCTION: This study characterizes ovariectomized (OVX)-induced osteoporotic fracture healing with focus on estrogen receptors (ERs). Callus formation plays a critical role in fracture healing, and ERs are well-known mechanosensors in osteogenic pathways. It was hypothesized that callus formation was related to and partially determined by the difference in expression patterns of ERs in both normal and OVX-induced osteoporotic fractures. METHODS: Closed femoral fracture in SHAM and ovariectomized rats were used in this study. Weekly callus width (CW) and area (CA), endpoint mechanical properties, gene expressions of Col-1, BMP-2, ER-α, ER-ß and ER-α:ER-ß ratios (ER-ratios), and correlations were assessed at 2, 4 and 8 weeks post-fracture. RESULTS: CW and CA results confirmed that OVX-induced osteoporotic fracture was delayed at 2-4 weeks with impaired endpoint mechanical properties. Gene expressions of ER-α and ER-ß were higher in the SHAM group at week 2 (p < 0.05) and later lowered at week 8; whereas the OVX group showed an opposing trend. Moderate correlation existed between ER-α and BMP-2 (0.545, p = 0.003), and ER-ratio and BMP-2 (0.601, p = 0.001), and BMP-2 to CW and CA (r = 0.709, p = 0.000 and r = 0.588, p = 0.001, respectively). ER-α and ER-ß proteins expressions were confirmed by immunohistochemistry at the fracture callus in reparative progenitor cells, osteoblasts- and osteoclasts-like cells. CONCLUSION: We conclude that the delayed healing rate and impaired callus quality in OVX-induced osteoporotic fracture is related to the delayed expression of ERs. A high ER-α:ER-ß ratio favors callus formation.

Wnt/ß-catenin signaling pathway as an important mediator in muscle and bone crosstalk: A systematic review.

Background: The interaction between muscle and bone is shown to be clinically important but the underlying mechanisms are largely unknown. The canonical Wnt/ß-catenin signaling pathway is reported to be involved in muscle-bone crosstalk, but its detailed function remains unclear. This systematic review aims to investigate and elucidate the role of the Wnt/ß-catenin signaling pathways in muscle-bone crosstalk. Methods: We conducted a literature search on the Web of Science, PubMed, EBSCO and Embase with keywords "Wnt*", "bone*" and "muscle*". A systematic review was completed according to the guideline of preferred reporting items of systematic reviews and meta-analyses (PRISMA). Data synthesis included species (human, animal or cell type used), treatments involved, outcome measures and key findings with respect to Wnts. Results: Seventeen papers were published from 2007 to 2021 and were extracted from a total of 1529 search results in the databases of Web of Science (468 papers), PubMed (457 papers), EBSCO (371) and Embase (233). 12 Wnt family members were investigated in the papers, including Wnt1, Wnt2, Wnt2b, Wnt3a, Wnt4, Wnt5a, Wnt8a, Wnt8b, Wnt9a, Wnt10a, Wnt10b and Wnt16. Many studies showed that muscles were able to increase or decrease osteogenesis of bone, while bone increased myogenesis of muscle through Wnt/ß-catenin signaling pathways. Wnt3a, Wnt4 and Wnt10b were shown to play important roles in the crosstalk between muscle and bone. Conclusions: Wnt3a, Wnt4 and Wnt10b are found to play important mediatory roles in muscle-bone crosstalk. The role of Wnt4 was mostly found to regulate muscle from the bone side. Whilst the role of Wnt10b during muscle ageing was proposed, current evidence is insufficient to clarify the specific role of Wnt/ß-catenin signaling in the interplay between sarcopenia and osteoporosis. More future studies are required to investigate the exact regulatory roles of Wnts in muscle-bone crosstalk in musculoskeletal disease models such as sarcopenia and osteoporosis. Translational potential of this article: The systematic review provides an extensive overview to reveal the roles of Wnt/ß-catenin signaling pathways in muscle-bone crosstalk. These results provide novel research directions to further understand the underlying mechanism of sarcopenia, osteoporosis, and their crosstalk, finally helping the future development of new therapeutic interventions.

Treatment effects, adverse outcomes and cardiovascular safety of romosozumab - Existing worldwide data: A systematic review and meta-analysis.

Background: Romosozumab is a novel monoclonal antibody that binds to sclerostin, and has dual effects of increasing bone formation and decreasing bone resorption, giving it a unique mechanism of action. The objective of this study was to perform a systematic review and meta-analysis based on existing worldwide data on treatment effects and safety of romosozumab in randomized controlled trials. Methods: A systematic search was carried out on four databases including PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL). The keywords used for search was "(romosozumab) AND (osteoporosis OR safety)". Randomized controlled trial or post-hoc studies of the included randomized controlled trial which studied the effects and safety of romosozumab were included. The quality of selected studies was assessed with the Cochrane collaboration tool and the PEDro scale. Results: 20 studies were included for qualitative analysis. 14 studies were included for meta-analysis. In total, there were 13,507 (n = 13,507) participants with 637 men and 12,870 women from original cohorts. The overall mean difference was in favor of romosozumab treatment for lumbar spine (10.04 (95 % confidence interval (CI) = 7.51-12.57; p < 0.00001)), total hip (4.04 (95 % CI = 3.10-4.99; p < 0.00001)) and femoral neck bone mineral density (3.77 (95 % CI = 2.90-4.64; p < 0.00001)) at 12 months. There was significantly less likelihood of new vertebral fractures with romosozumab compared to control (odds ratio (OR) 0.42 (95 % CI = 0.20-0.89); p = 0.02) at 12 months of treatment. There was significantly less likelihood of new vertebral fracture at 24 months with 12 months of romosozumab followed by sequential treatment with anti-resorptive compared to control with only anti-resorptive agent use (OR 0.36 (95 % CI = 0.18-0.71); p = 0.003). There was no significant difference in serious adverse events and fatal adverse events with use of romosozumab compared with control in our meta-analyses. There were no significant differences in serious cardiovascular events in Asian population of romosozumab with control group with 12 months of romosozumab treatment followed by 24 months of anti-resorptive agent with OR 1.09 (95 % CI = 0.40-2.96; P = 0.86). There was no significant difference between romosozumab group and control group for the median time to radiographic healing. Our qualitative analysis on Quantitative Computed Tomography (QCT), Finite element analysis (FEA) and bone biopsy analyses demonstrated that romosozumab improved parameters and measures in these domains as well. Conclusion: In conclusion, our study showed that romosozumab was an effective agent to treat osteoporosis with high quality evidence. There were no significant differences in the adverse events, serious adverse events, fatal adverse events identified. Further subgroup analysis of cardiovascular events and cardiovascular death in the total population showed no differences either. The translational potential of this article: Given the results, romosozumab is an effective agent to treat patients with very-high risk of osteoporotic fractures.

Implants coating strategies for antibacterial treatment in fracture and defect models: A systematic review of animal studies.

Objective: Fracture-related infection (FRI) remains a major concern in orthopaedic trauma. Functionalizing implants with antibacterial coatings are a promising strategy in mitigating FRI. Numerous implant coatings have been reported but the preventive and therapeutic effects vary. This systematic review aimed to provide a comprehensive overview of current implant coating strategies to prevent and treat FRI in animal fracture and bone defect models. Methods: A literature search was performed in three databases: PubMed, Web of Science and Embase, with predetermined keywords and criteria up to 28 February 2023. Preclinical studies on implant coatings in animal fracture or defect models that assessed antibacterial and bone healing effects were included. Results: A total of 14 studies were included in this systematic review, seven of which used fracture models and seven used defect models. Passive coatings with bacteria adhesion resistance were investigated in two studies. Active coatings with bactericidal effects were investigated in 12 studies, four of which used metal ions including Ag+ and Cu2+; five studies used antibiotics including chlorhexidine, tigecycline, vancomycin, and gentamicin sulfate; and the other three studies used natural antibacterial materials including chitosan, antimicrobial peptides, and lysostaphin. Overall, these implant coatings exhibited promising efficacy in antibacterial effects and bone formation. Conclusion: Antibacterial coating strategies reduced bacterial infections in animal models and favored bone healing in vivo. Future studies of implant coatings should focus on optimal biocompatibility, antibacterial effects against multi-drug resistant bacteria and polymicrobial infections, and osseointegration and osteogenesis promotion especially in osteoporotic bone by constructing multi-functional coatings for FRI therapy. The translational potential of this paper: The clinical treatment of FRI is complex and challenging. This review summarizes novel orthopaedic implant coating strategies applied to FRI in preclinical studies, and offers a perspective on the future development of orthopaedic implant coatings, which can potentially contribute to alternative strategies in clinical practice.

Prevention of age-related neuromuscular junction degeneration in sarcopenia by low-magnitude high-frequency vibration.

Neuromuscular junction (NMJ) degeneration is one of pathological factors of sarcopenia. Low-magnitude high-frequency vibration (LMHFV) was reported effective in alleviating the sarcopenia progress. However, no previous study has investigated treatment effects of LMHFV targeting NMJ degeneration in sarcopenia. We first compared morphological differences of NMJ between sarcopenic and non-sarcopenic subjects, as well as young and old C57BL/6 mice. We then systematically characterized the age-related degeneration of NMJ in SAMP8 against its control strain, SAMR1 mice, from 3 to 12 months old. We also investigated effects of LMHFV in SAMP8 on the maintenance of NMJ during the onset of sarcopenia with respect to the Agrin-LRP4-MuSK-Dok7 pathway and investigated the mechanism related to ERK1/2 signaling. We observed sarcopenic/old NMJ presented increased acetylcholine receptors (AChRs) cluster fragmentation and discontinuity than non-sarcopenic/young NMJ. In SAMP8, NMJ degeneration (morphologically at 6 months and functionally at 8 months) was observed associated with the sarcopenia onset (10 months). SAMR1 showed improved NMJ morphology and function compared with SAMP8 at 10 months. Skeletal muscle performance was improved at Month 4 post-LMHFV treatment. Vibration group presented improved NMJ function at Months 2 and 6 posttreatment, accompanied with alleviated morphological degeneration at Month 4 posttreatment. LMHFV increased Dok7 expression at Month 4 posttreatment. In vitro, LMHFV could promote AChRs clustering in myotubes by increasing Dok7 expression through suppressing ERK1/2 phosphorylation. In conclusion, NMJ degeneration was observed associated with the sarcopenia onset in SAMP8. LMHFV may attenuate NMJ degeneration and sarcopenia progression by increasing Dok7 expression through suppressing ERK1/2 phosphorylation.

Effects of physical exercise on neuromuscular junction degeneration during ageing: A systematic review.

The neuromuscular junction (NMJ) is a specialized chemical synapse that converts neural impulses into muscle action. Age-associated NMJ degeneration, which involves nerve terminal and postsynaptic decline, denervation, and loss of motor units, significantly contributes to muscle weakness and dysfunction. Although physical training has been shown to make substantial modifications in NMJ of both young and aged animals, the results are often influenced by methodological variables in existing studies. Moreover, there is still lack of strong consensus on the specific effects of exercise on improving the morphology and function of the ageing NMJ. Consequently, the purpose of this study was to conduct a systematic review to elucidate the effects of exercise training on NMJ compartments in the elderly. We conducted a systematic review using PubMed, Embase, and Web of Science databases, employing relevant keywords. Two independent reviewers selected studies that detailed NMJ changes during exercise in ageing, written in English, and available in full text. In total, 20 papers were included. We examined the altered adaptation of the NMJ to exercise, focusing on presynaptic and postsynaptic structures and myofibers in older animals or humans. Our findings indicated that aged NMJs exhibited different adaptive responses to physical exercise compared to younger counterparts. Endurance training, compared with resistance and voluntary exercise regimens, was found to have a more pronounced effect on NMJ structural remodeling, particularly in fast twitch muscle fibers. Physical exercise was observed to promote the formation and maintenance of acetylcholine receptor (AChR) clusters by increasing the recombinant docking protein 7 (Dok7) expression and stabilizing Agrin and lipoprotein receptor-related protein 4 (LRP4). These insights suggest that research on exercise-related therapies could potentially attenuate the progression of neuromuscular degeneration. Translational potential of this article: This systematic review provides a detailed overview of the effects of different types of physical exercise on improving NMJ in the elderly, providing scientific support for the timely intervention of muscle degeneration in the elderly by physical exercise, and providing help for the development of new therapeutic interventions in the future.

Biophysical and nutritional combination treatment for myosteatosis in patients with sarcopenia: a study protocol for single-blinded randomised controlled trial.

INTRODUCTION: Sarcopenia is characterised by age-related loss of skeletal muscle and function and is associated with risks of adverse outcomes. The prevalence of sarcopenia increases due to ageing population and effective interventions is in need. Previous studies showed that ß-hydroxy ß-methylbutyrate (HMB) supplement and vibration treatment (VT) enhanced muscle quality, while the coapplication of the two interventions had further improved muscle mass and function in sarcopenic mice model. This study aims to investigate the efficacy of this combination treatment in combating sarcopenia in older people. The findings of this study will demonstrate the effect of combination treatment as an alternative for managing sarcopenia. METHODS AND ANALYSIS: In this single-blinded randomised controlled trial, subjects will be screened based on the Asian Working Group for Sarcopenia (AWGS) 2019 definition. 200 subjects who are aged 65 or above and identified sarcopenic according to the AWGS algorithm will be recruited. They will be randomised to one of the following four groups: (1) Control+ONS; (2) HMB+ONS; (3) VT+ONS and (4) HMB+VT + ONS, where ONS stands for oral nutritional supplement. ONS will be taken in the form of protein formular once/day; HMB supplements will be 3 g/day; VT (35 Hz, 0.3 g, where g=gravitational acceleration) will be received for 20 mins/day and at least 3 days/week. The primary outcome assessments are muscle strength and function. Subjects will be assessed at baseline, 3-month and 6-month post treatment. ETHICS AND DISSEMINATION: This study was approved by Joint CUHK-NTEC (The Chinese University of Hong Kong and New Territories East Cluster) Clinical Research Management Office (Ref: CRE-2022.223-T) and conformed to the Declaration of Helsinki. Trial results will be published in peer-reviewed journals and disseminated at academic conferences. TRIAL REGISTRATION NUMBER: NCT05525039.

Application of image recognition-based tracker-less augmented reality navigation system in a series of sawbone trials.

BACKGROUND: This study introduced an Augmented Reality (AR) navigation system to address limitations in conventional high tibial osteotomy (HTO). The objective was to enhance precision and efficiency in HTO procedures, overcoming challenges such as inconsistent postoperative alignment and potential neurovascular damage. METHODS: The AR-MR (Mixed Reality) navigation system, comprising HoloLens, Unity Engine, and Vuforia software, was employed for pre-clinical trials using tibial sawbone models. CT images generated 3D anatomical models, projected via HoloLens, allowing surgeons to interact through intuitive hand gestures. The critical procedure of target tracking, essential for aligning virtual and real objects, was facilitated by Vuforia's feature detection algorithm. RESULTS: In trials, the AR-MR system demonstrated significant reductions in both preoperative planning and intraoperative times compared to conventional navigation and metal 3D-printed surgical guides. The AR system, while exhibiting lower accuracy, exhibited efficiency, making it a promising option for HTO procedures. The preoperative planning time for the AR system was notably shorter (4 min) compared to conventional navigation (30.5 min) and metal guides (75.5 min). Intraoperative time for AR lasted 8.5 min, considerably faster than that of conventional navigation (31.5 min) and metal guides (10.5 min). CONCLUSIONS: The AR navigation system presents a transformative approach to HTO, offering a trade-off between accuracy and efficiency. Ongoing improvements, such as the incorporation of two-stage registration and pointing devices, could further enhance precision. While the system may be less accurate, its efficiency renders it a potential breakthrough in orthopedic surgery, particularly for reducing unnecessary harm and streamlining surgical procedures.

Does the regulation of skeletal muscle influence cognitive function? A scoping review of pre-clinical evidence.

Background: Cognitive impairment is a major challenge for elderlies, as it can progress in a rapid manner and effective treatments are limited. Sarcopenic elderlies have a higher risk of dementia. This scoping review aims to reveal whether muscle is a mediator of cognitive function from pre-clinical evidence. Methods: PubMed, Embase, and Web of Science were searched to Feb 2nd, 2022, using the keywords (muscle) AND (cognition OR dementia OR Alzheimer) AND (mouse OR rat OR animal). The PRISMA guideline was used in this study. Results: A total of 17 pre-clinical studies were selected from 7638 studies. 4 studies reported that muscle atrophy and injury harmed memory, functional factors, and neurons in the brain for rodents with or without Alzheimer's disease (AD). 3 studies observed exercise induced muscle to secrete factors, including lactate, fibronectin type III domain-containing protein 5 (FNDC5), and cathepsin B, which plays essential roles in the elevation of cognitive functions and brain-derived neurotrophic factor (BDNF) levels. Muscle-targeted treatments including electrical stimulation and intramuscular injections had effective remote effects on the hippocampus. 6 studies showed that muscle-specific overexpression of scFv59 and Neprilysin, or myostatin knockdown alleviated AD symptoms. 1 study showed that muscle insulin resistance also led to deficient hippocampal neurogenesis in MKR mice. Conclusions: The skeletal muscle is involved in the mediation of cognitive function. The evidence was established by the response in the brain (altered number of neurons, functional factors, and other AD pathological characteristics) with muscle atrophy or injury, muscle secretory factors, and muscle-targeted treatments. The translational potential of this paper: This study summarizes the current evidence in how muscle affects cognition in molecular levels, which supports muscle-specific treatments as potential clinical strategies to prevent cognitive dysfunction.

Potential of Fatty Acids in Treating Sarcopenia: A Systematic Review.

This paper presents a systematic review of studies investigating the effects of fatty acid supplementation in potentially preventing and treating sarcopenia. PubMed, Embase, and Web of Science databases were searched using the keywords 'fatty acid' and 'sarcopenia'. Results: A total of 14 clinical and 11 pre-clinical (including cell and animal studies) studies were included. Of the 14 clinical studies, 12 used omega-3 polyunsaturated fatty acids (PUFAs) as supplements, 1 study used ALA and 1 study used CLA. Seven studies combined the use of fatty acid with resistant exercises. Fatty acids were found to have a positive effect in eight studies and they had no significant outcome in six studies. The seven studies that incorporated exercise found that fatty acids had a better impact on elderlies. Four animal studies used novel fatty acids including eicosapentaenoic acid, trans-fatty acid, and olive leaf extraction as interventions. Three animal and four cell experiment studies revealed the possible mechanisms of how fatty acids affect muscles by improving regenerative capacity, reducing oxidative stress, mitochondrial and peroxisomal dysfunctions, and attenuating cell death. Conclusion: Fatty acids have proven their value in improving sarcopenia in pre-clinical experiments. However, current clinical studies show controversial results for its role on muscle, and thus the mechanisms need to be studied further. In the future, more well-designed randomized controlled trials are required to assess the effectiveness of using fatty acids in humans.

Study on the Optimal Surgical Scheme for Very Severe Osteoporotic Vertebral Compression Fractures.

OBJECTIVE: Therapy of very severe osteoporotic compression fractures (VSOVCF) has been a growing challenge for spine surgeons. Opinions vary regarding the optimal surgical procedure for the treatment of VSOVCF and which internal fixation method is more effective is still under debate, and research on this topic is lacking. This retrospective study was conducted to compare the efficacy and safety of various pedicle screw fixation methods for treating VSOVCF. METHODS: This single-center retrospective comparative study was conducted between January 2015 and September 2020. Two hundred and one patients were divided into six groups according to different surgical methods: 45 patients underwent long-segment fixation (Group 1); 39 underwent short-segment fixation (Group 2); 30 received long-segment fixation with cement-reinforced screws (Group 3); 32 received short-segment fixation with cement-reinforced screws (Group 4); 29 had long-segment fixation combined with kyphoplasty (PKP) (Group 5); and 26 cases had short-segment fixation combined with PKP (Group 6). The clinical records were reviewed and the visual analogue scale (VAS) score and the Oswestry Disability Index (ODI) score were used for clinical evaluation. The vertebral height (VH), fractured vertebral body height (FVBH), and Cobb's angle were objectively calculated and analyzed on lateral plain radiographs. Student's t-tests and one-way ANOVA among groups were conducted to analyze the continuous, and the chi-squared test was used to compare the dichotomous or categorical variables. The difference was considered statistically significant when the P-value was less than 0.05. RESULTS: The six groups had similar distributions in age, gender, course of the disease, follow-up period, and injured level. In the postoperative assessment of the VAS score, the surgical intervention most likely to rank first in terms of pain relief was the short-segment fixation with cement-reinforced screws (Group 4). For the functional evaluation, the surgical intervention that is most likely to rank first in terms of ODI score was a short-segment fixation with cement-reinforced screws (Group 4), followed by long-segment fixation (Group 1). The long-segment fixation with cement-reinforced screws was the first-ranked surgical intervention for the maintenance of Cobb's angle and vertebral height, whereas the short-segment fixation performed the worst. The highest overall complication rate was in Group 6 with an incidence of 42.3% (11/26), followed by Group 2 with an incidence of 38.5% (15/39). CONCLUSION: For the treatment of VSOVCF, the short-segment fixation with cement-reinforced screws is the most effective and optimal procedure, and should be used as the preferred surgical method if surgeons are proficient in using cemented screws; otherwise, directly and unquestionably use long-segment fixation to achieve satisfactory clinical results.