BACKGROUND:Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD-causing mutation in humans is exon 52 deletion (DMDΔ52), which disrupts the reading frame and abolishes dystrophin expression. Therapeutic skipping of exon 51 or 53 can restore the reading frame, producing a truncated but functional protein and generating a BMD-like phenotype. Porcine models recapitulating DMDΔ52 (DMD) and DMDΔ51-52 (BMD-like) were used to identify molecular differences and condition-specific miRNA-mRNA networks. METHODS:Skeletal muscle (triceps brachii) from four DMD, four BMD, and five wild-type (WT) pigs at 3.5 months of age underwent stranded total RNA-seq and small RNA-seq. Differentially expressed mRNAs (|log2FC| ≥ 1, adj. p ≤ 0.05) and miRNAs (adj. p ≤ 0.05) were identified with DESeq2. miRNA-mRNA networks were constructed using RNAhybrid predictions (MFE < -25 kcal/mol, seed pairing) filtered by inverse Pearson correlation. RESULTS:Compared with WT, DMD muscle exhibited 1440 upregulated and 487 downregulated genes, characterized by strong repression of structural, contractile, calcium-handling and metabolic genes (e.g., MYBPC2, MYL3, MYLK2, CACNA2D3, CACNA2D4) and marked upregulation of inflammatory mediators and innate immune receptors (e.g., IL6, IL18, IL1R1, CCR1/2/5, TLR1/2/4/7/9). In contrast, BMD muscle showed partial restoration of these pathways and clustered closer to WT in global expression profiles. Distinct miRNA signatures were observed between DMD and BMD. Differential expression analysis identified 22 upregulated and 12 downregulated miRNAs in DMD versus WT and 36 upregulated and 21 downregulated miRNAs in BMD versus WT. Integration of miRNA and mRNA data yielded extensive regulatory networks (1013 unique pairs for upregulated miRNAs in DMD; 2679 pairs for downregulated miRNAs in BMD). Two condition-specific miRNAs emerged as strong biomarker candidates: ssc-miR-296-3p (upregulated exclusively in DMD, targeting 228 genes enriched in muscle structure and fatty acid metabolism) and ssc-miR-423-5p (elevated specifically in BMD, targeting 67 genes involved in calcium signalling and tissue development). Several dysregulated miRNAs, including miR-199a-5p and miR-199b, overlapped with those reported in human DMD and other muscular dystrophies. CONCLUSIONS:Exon 51 skipping in the DMDΔ52 background partially restores key transcriptional programmes in skeletal muscle but does not fully normalize them to WT patterns. The identification of condition-specific miRNAs highlights post-transcriptional regulatory differences between DMD and BMD, positioning them as promising biomarkers and therapeutic targets. These findings underscore the translational value of porcine dystrophinopathy models for mechanistic studies and preclinical evaluation of RNA-targeted interventions.
BACKGROUND:Age-related declines in energy metabolism, muscle strength and physical performance have been linked to lower mitochondrial respiratory capacity. Peripheral blood mononuclear cell (PBMC) respiration offers a minimally invasive marker of systemic bioenergetics, yet its relationship to whole-body metabolic flexibility remains unclear. This study examined whether PBMC respiratory capacity is associated with substrate utilization during submaximal exercise, muscle strength and physical function in healthy older adults. METHODS:PBMC mitochondrial respiratory capacity was quantified by high-resolution respirometry assessing ROUTINE, LEAK and MAX states. Postprandial substrate oxidation during steady-state treadmill walking at 60% of VO2max (oxygen uptake) was quantified by indirect calorimetry, and fat and carbohydrate oxidation rates were calculated using standard stoichiometric equations. Metabolic flexibility was defined as lower respiratory exchange ratio (RER) and higher relative fat oxidation at a fixed workload. Muscle strength was determined by handgrip dynamometry and one-repetition maximum leg extension. Physical function was evaluated by gait speed and five-repetition chair rise time. Associations were tested with linear and logistic regression adjusted for age, sex, skeletal muscle index, physical activity and high-sensitive C-reactive protein concentrations. Exploratory K-means clustering identified mitochondrial respiration phenotypes. RESULTS:Fifty community-dwelling older adults (22 men, 28 women; age 70 ± 4 years) were examined. Higher ROUTINE respiration was correlated with RER (rho = -0.335, p = 0.020), fat utilization (rho = -0.334, p = 0.019), grip strength (rho = 0.302, p = 0.033) and gait speed (rho = 0.324, p = 0.022). Adjusted regression analyses confirmed the association of ROUTINE respiration with greater fat oxidation (β = 0.212, 95% CI 0.049; 0.375), lower RER (β = -0.160, 95% CI -0.300; -0.020) and higher gait speed (β = 0.153, 95% CI 0.028; 0.277). Similar associations were found for ATP-linked respiration. Cluster analysis identified high- and low-respiration phenotypes. Compared with the high-respiration group the low-respiration group showed lower CMJ height (OR: 0.204, 95% CI 0.055; 0.763) and quadriceps strength (OR: 0.373, 95% CI 0.155; 0.897). CONCLUSIONS:In healthy older adults, higher PBMC ROUTINE respiration was associated with a more fat-dominant substrate utilization profile during submaximal exercise, greater muscle strength and faster gait speed. PBMC respiratory capacity may reflect systemic bioenergetic status relevant to exercise substrate utilization and physical performance in ageing.
BACKGROUND:Ultra-endurance sports are increasingly popular, yet the long-term physiological consequences of sustained extreme training loads remain poorly understood. In particular, the effects of prolonged ultra-endurance exercise on skeletal muscle structure, function and molecular remodelling are largely unknown. This case study examined a highly experienced ultra-endurance athlete who completed a world-record attempt to run 30 300 km, with extensive phenotyping focusing on skeletal muscle adaptations and recovery. METHODS:A 49-year-old male athlete (172 cm, 65 kg) ran ~70 km daily for 15 months. Musculoskeletal, cardiac and visceral ultrasonography, leg muscle strength and power measurements were performed before and after the challenge. Muscle biopsies (n = 4) from vastus lateralis were obtained immediately after completion and during 17 months of recovery to assess myosin heavy chain (MHC) composition, mitochondrial electron transport chain (ETC) complexes and proteins involved in mitochondrial turnover, autophagy and inflammation. Body composition, haematological and biochemical markers, and gut microbiota composition were monitored longitudinally. RESULTS:The athlete ran 30 300 km over 444 days, maintaining a daily distance of ~70 km despite substantial musculoskeletal discomfort, including a tibial stress reaction mid-challenge, which resolved gradually with continued running. Body mass decreased by ~3 kg, primarily reflecting fat loss (~83%), accompanied by reductions in muscle thickness, maximal strength and power. Circulating creatine kinase (3-15-fold), oxidative stress markers (~50%) and GDF8 (~10%-50%) were sustainedly increased, whereas IGF-I decreased (~10%-40%), suggesting a reduced anabolic environment during the challenge. Muscle biopsy analyses revealed a progressive recovery of mitochondrial function during the 17 months following the challenge, as evidenced by a progressive increase in ETC protein abundance and the expression of regulators of mitochondrial dynamics and quality control (MFN2, PARKIN, DRP1). In contrast, markers of autophagy, apoptosis and inflammation were decreased during the 17-months post-challenge (LC3A/B-I by ~50%, CASP3 by ~60% and NF-κBSer536 by ~20%). Muscle fibre composition showed extreme predominance of slow fibres (nearly 100% MHC-I), which persisted during recovery. Most molecular and functional alterations gradually resolved within 10-17 months. Gut microbiota diversity increased during the challenge, with enrichment of Bifidobacterium during running and Akkermansia during recovery. CONCLUSIONS:Sustaining daily ultrarunning for more than 1 year induces substantial skeletal muscle remodelling, including reduced muscle size, impaired contractile function and mitochondrial maladaptations, despite largely preserved endocrine and haematological stability. These findings highlight skeletal muscle as a primary physiological system challenged during extreme endurance exercise and demonstrate that recovery from such perturbations may require more than one year.
BACKGROUND:Skeletal muscle injuries significantly impair mobility and function, yet effective therapeutic interventions remain limited. Both eccentric exercise (EE) and concentric exercise (CE) promote muscle repair, but the underlying mechanisms are not fully understood. Muscle-derived extracellular vesicles (mEVs) have emerged as critical mediators of intercellular communication; however, their role in exercise-induced regeneration remains unclear. METHODS:A murine model of barium chloride-induced muscle injury was used to compare the effects of EE and CE on muscle regeneration. mEVs were isolated from sedentary (SED), CE- and EE-conditioned muscle and characterised by nanoparticle tracking analysis, transmission electron microscopy and western blotting. Metabolic profiling of mEVs was performed using LC-MS. The functional roles were assessed through intramuscular injection of mEVs and GW4869-mediated inhibition of mEV secretion. The effects of mEVs on myogenesis were further examined in C2C12 myoblasts. RESULTS:EE significantly enhanced muscle regeneration compared with CE, as evidenced by improved histology, reduced fibrosis (F (2,15) = 59.37, p < 0.0001) and increased expression of myogenic markers such as Myod (p < 0.001), Myog (p < 0.001) and eMyhc (p < 0.001). EE also induced greater release of mEVs than CE, as indicated by higher expression of mEV markers and Rab27a/b (Rab27a, p < 0.001; Rab27b, p = 0.1222). Inhibition of mEV secretion with GW4869 abolished the regenerative benefits of exercise. Exogenous administration of EE-mEVs enhanced muscle repair and C2C12 differentiation (Myod, F (2, 6) = 33.09, p < 0.001; Myog, F (2, 6) = 66.41, p < 0.001) more effectively than CE-mEVs or SED-mEVs. Metabolomic analysis revealed significant enrichment of lipid metabolites in EE-mEVs (N = 5, p < 0.05), which was consistent with the upregulation of lipid metabolism-related genes. RNA-seq analyses further indicated that lipid metabolites enriched in mEVs contributed to muscle repair potentially through activation of energy-sensing pathways such as AMPK. CONCLUSIONS:EE facilitates muscle repair more effectively than CE by promoting the release of mEVs enriched in pro-regenerative lipid metabolites. These findings suggest EE-mEVs as a promising biological therapeutic strategy for muscle injury, particularly in cases where exercise is not feasible.
ABSTRACT Background and Aim Among the oldest‐old, the impact of body composition on survival outcomes exhibits pronounced heterogeneity. Although the obesity paradox has been widely discussed, clear evidence is still lacking regarding whether the biological effects of adipose reserves are modulated by functional status. Therefore, this study aims to investigate the association between adipose reserve indicators and long‐term all‐cause mortality risk in the oldest‐old and to elucidate the regulatory role of frailty, thereby providing an evidence‐based foundation for precision clinical health management. Methods This prospective cohort study included 529 community‐dwelling oldest‐old individuals. Participants were categorized into prefrailty and frailty groups at baseline using the Fried frailty phenotype. Bioelectrical impedance analysis was utilized to measure body composition. Stratified multivariate Cox proportional hazards regression models were employed to evaluate the relationship between adipose indicators and all‐cause mortality. Additionally, restricted cubic splines (RCS) and Kaplan–Meier curves were used to analyse survival heterogeneity. Results During a median follow‐up of 3.84 years, 88 deaths (16.6%) occurred. In the prefrail oldest‐old, adipose reserves exhibited significant protective effects on survival: The fully adjusted model showed that PBF (HR = 0.92, 95% CI: 0.87–0.98, p = 0.006), VFA (HR = 0.99, 95% CI: 0.97–0.99, p = 0.013) and WHR (HR = 0.91, 95% CI: 0.86–0.95, p < 0.001) were all inversely associated with mortality risk. In contrast, these protective effects vanished in the frail oldest‐old (all p > 0.05), suggesting that the benefits of adipose tissue are contingent upon the individual's basal functional reserve. RCS analysis revealed a linear dose–response relationship between adipose indicators and mortality risk (all p for non‐linearity > 0.05), with no significant threshold effect observed. Interaction analyses confirmed that frailty status significantly modulated the prognostic value of adipose metrics (p < 0.05), with protective effects restricted exclusively to prefrail individuals. Kaplan–Meier curves confirmed that individuals in the prefrailty stage with higher adipose reserves achieved the highest survival rates (all Log‐rank p < 0.001). Conclusion These findings suggest that the protective effect of adipose reserves is frailty‐dependent in the oldest‐old, and that weight management strategies should consider baseline functional status.
ABSTRACT Background Critically ill patients frequently experienced acquired muscle dysfunction, which adversely affects outcomes. The relationship between calorie intake, muscle dysfunction and outcomes remains unclear. This study aims to determine if early calorie intake affects patients' outcomes through changes in skeletal muscle mass or quality, and to explore changes in muscle structure and underlying molecular pathways using limb muscle biopsies in a piglet model. Methods This translational study combines data from a prospective observational study including critically ill patients and a 72‐h ventilated piglet model with early high calorie full enteral nutrition, both recording serial ultrasound measurements of limb muscle thickness and stiffness. Patients were classified into two trajectory groups based on thickness, stiffness and calorie intake. Adjusted mediation analysis quantified the effect of calorie intake on outcomes explained by muscle trajectories. The primary endpoint was ventilator‐free days at Day 28 (VFD28). In vivo limb muscle biopsies from piglets were analysed. Results Among 102 patients, 21% and 28% exhibited decreased thickness and stiffness by Day 7, respectively; 36% received high‐calorie intake at Day 7. Patients categorized into the ‘decreased trajectory group’ for both thickness and stiffness showed lower VFD28 (p < 0.01) and longer ICU stay (p < 0.01) compared to the ‘stable trajectory group’. High‐calorie intake was associated with significantly lower VFD28 (−8.7 days [−14.7 to −1.7]; p = 0.01), longer ICU stay (p < 0.01) and higher ICU mortality (p < 0.01). Decreased muscle trajectories mediated, respectively, 42% and 28% of the association between high‐calorie intake and VFD 28. The porcine model showed a limb muscle stiffness reduction associated with muscle fibre atrophy and increased intramuscular lipid content linked to decreased protein synthesis (IGF‐1 and myostatin downregulation), increased autophagy (ATG5, ATG7 and P62 increased activity) and impaired fatty acid metabolism (carnitine palmitoyltransferase 1B reduced expression). Conclusions This study demonstrates that early calorie intake in critically ill patients adversely affects muscle mass and quality, mediating negative outcomes. The porcine model helps elucidate underlying mechanisms, with early high‐calorie intake resulting in a metabolic oversupply state associated with metabolic disorders leading to muscle fibre atrophy and lipid accumulation. These results highlight the importance of targeted nutritional strategies to preserve muscle health in critically ill patients.
ABSTRACT Background Oesophageal cancer remains the sixth most lethal malignancy, with 5‐year survival rates around 22%. CT‐derived 2D body composition analysis has emerged as a promising prognostic tool, but conventional, often manually created single‐slice L3 measurements are unsuited for future clinical implementation. We evaluated fully automated AI‐derived volumetric body composition indices as prognostic parameters using conventional L3 and BMI measurements as reference. Methods This retrospective cohort study included patients with histologically confirmed oesophageal cancer treated between 2011 and 2024. Automated deep learning segmentation using the nnU‐Net‐based body and organ analysis pipeline quantified abdominal tissue volumes from staging CTs. Three normalized indices were calculated: sarcopenia index (SI, muscle/bone volume ratio), myosteatotic fat index (MFI, intramuscular/total adipose tissue volume ratio) and abdominal fat index (AFI, visceral/subcutaneous adipose tissue volume ratio). Cox proportional hazards models assessed prognostic value after sequential adjustment for age, sex, metastatic status, ECOG performance status, BMI and L3‐derived indices. Kaplan–Meier analysis evaluated survival differences stratified by sex‐specific median values. Results The cohort comprised 563 patients (19.7% female), median age 65.4 years (IQR: 58.8–71.3); 10.1% (n = 57) had metastatic disease and 68.7% (n = 387) underwent surgery. Males had higher sarcopenia index (2.54 ± 0.41 vs. 2.24 ± 0.45, p < 0.001) and abdominal fat index (median 0.72 vs. 0.36, p < 0.001), whereas MFI showed no difference (p = 0.89). During median follow‐up of 22 months, 367 deaths (65.9%) occurred. Median overall survival was 28.6 months (95% CI: 23.7–33.3); 1‐year survival 70.7% (95% CI: 67.2%–74.8%) and 5‐year survival 32.8% (95% CI: 29.6%–38.3%), with marked differences by metastatic status (M0 vs. M1 1‐year survival: 73.4% vs. 46.4%). In the fully adjusted model incorporating all three volumetric indices alongside clinical covariates, BMI and L3‐derived parameters (n = 532), only sarcopenia index retained independent significance (HR = 0.56, 95% CI: 0.37–0.82, p = 0.003); all others showed p ≥ 0.26. Metastatic status (HR = 2.23, p < 0.001) and ECOG (HR = 1.29, p < 0.001) remained significant. All L3 indices lost significance alongside volumetric parameters (p > 0.14). Male patients with high sarcopenia index showed longer survival compared with patients with low sarcopenia index (33.3 vs. 21.8 months, p < 0.001); female patients showed larger descriptive contrasts (68.8 vs. 16.8 months, p < 0.001) that were formally confirmed by a significant sex‐SI Cox interaction (LRT p = 0.026). Conclusions Automatic AI‐derived volumetric body composition parameters calculated from routine staging CTs predict overall survival in patients with oesophageal cancer and are associated with sex‐related differences of prognostic impact, supporting further evaluation toward future clinical use.
ABSTRACT Background The molecular mechanisms underlying frailty are under intense investigation. Independent observational studies revealed various biological processes and biomarkers differentially expressed in frail individuals and after interventions. Recently, several transcriptomic approaches have described molecular patterns associated with frailty status. However, the effects of physical exercise interventions remain unexplored. Two studies (FRAILOMIC and BIOFRAIL) identified molecular signatures associated with frailty. The objective of the study was to analyse the expression of the FRAILOMIC and BIOFRAIL biomarkers following a multicomponent personalized exercise intervention in older adults. Methods A multi‐centre study included a control (n = 24, with 14 women and 10 men, median age 80 ± 5) and an exercise intervention group (n = 44, with 38 women and 6 men, median age 79 ± 4). The latter underwent a 16‐week multicomponent presential physical exercise programme; clinical, functional and frailty assessments were performed before and after the intervention in both groups. Latent class analysis identified ‘responders’ and ‘non‐responders’ to the intervention. Data in a testosterone‐suppressed control cohort of older men with prostatic cancer receiving androgen deprivation therapy (n = 21) were included. Molecular biomarkers were measured via qRT‐PCR and ELISA. Results The exercise group presented improvements in functional capacity, as shown by Short Physical Performance Battery (SPPB) (post‐ 10.1 vs. 9.1 in pre‐intervention), grip strength (18.3 vs. 16.9 kg), gait speed (0.85 vs. 0.78 m/s), sarcopenia (2.1 vs. 3.0) and frailty status by Fried Frailty Phenotype (1.6 vs 2.1 criteria) (all ≤ 0.004). ANCOVA revealed significant improvements in SPPB (p = 0.04) and grip strength (p < 0.005) with exercise. Four of the six FRAILOMIC biomarkers (miR125b, miR194, RAGE and Troponin) and six of seven BIOFRAIL biomarkers (EGR1, CXCL8, GOS2, NSF, DDX11L1 and miR454) reversed significantly their expression after exercise training (p ≤ 0.05 for FRAIOLMIC and ≤ 0.01 for BIOFRAIL respectively). In contrast, these changes were not observed in testosterone‐suppressed controls, who experienced muscle loss. Latent class analysis revealed 36 ‘responders’ (with 32 cases from intervention group) and 29 ‘non‐responders’. Logistic regression showed that miR454, EGR1, DDX11L1 and Troponin displayed the strongest predictive value in distinguishing responders from non‐responders. Conclusions Exercise intervention improved functional status and reversed biological frailty, as evidenced by changes in multiple MultiOMIC frailty biomarkers. Among these, the BIOFRAIL trio—miR454, EGR1 and DDX11L1—showed the strongest predictive power for intervention response with AUC of 0.83. This study provides proof‐of‐concept for the utility of OMIC‐derived frailty biomarkers as outcome measures after intervention.
ABSTRACT Background Ageing is associated with anthropometric changes that have been linked to functional limitations and disease risk. However, previous work is limited to a few anthropometric measures, such as body mass index or waist‐to‐height ratio. Current imaging technology allows a rapid, burden‐free and simultaneous assessment of multidimensional anthropometry. What anthropometric measures can predict chronological age and whether the anthropometric age gap (AAG) further predicts health outcomes beyond chronological ageing have not been previously studied. The identification of age‐related anthropometric measures could be used clinically to identify individuals who undergo accelerated anthropometric ageing and may be at risk of developing adverse health outcomes. Methods In 302 Baltimore Longitudinal Study of Aging participants, each participant had 171 body anthropometric measurements collected (mean: 71.7 ± 13.4 years [27–95], 58% women, 30% Black, mean body mass index: 27.4 ± 4.5 kg/m2) using a 3D body scanner (Vitus by Human Solutions GmbH, Kaiserslautern, Germany). We used a LASSO machine learning model to identify anthropometric measures that jointly predicted chronological age after adjusting for sex, race and total body height. We further used covariate‐adjusted linear mixed‐effects models to examine whether the gap between anthropometric‐predicted age and chronological age (AAG) would predict concurrent cognitive/physical functions and body composition, as well as longitudinal changes over the past 20 years (mean follow‐up: 13 ± 5 years). Results The LASSO regression identified 22 anthropometric measures associated with chronological age (R2 = 0.689, mean absolute error = 4.5 years), notably lower thigh girth, waist‐to‐buttock length and calf girth with older age. Greater AAG was cross‐sectionally associated with lower cognitive scores related to motor planning, lower physical function and lower extremity body mass (all p < 0.05). Great AAG was also associated with accelerated declines in sensorimotor functions, including manual dexterity, balance and eccentric muscle strength, and greater loss of lower extremity lean and fat mass (all p < 0.05). Conclusions Accelerated anthropometric ageing, involving key age‐related measures, is associated with longitudinal declines in sensorimotor and muscle function. Anthropometric features that change with ageing may indicate loss of motor control, mobility and muscle function. Future studies are warranted to understand the mechanistic underpinnings of the associations with health outcomes.
ABSTRACT Background A loss of muscle mass and strength is a marker of poor outcomes following surgery. Changes in muscle gene expression following surgery are likely to contribute to postsurgical muscle loss, but the mechanisms controlling these changes are not known. We have previously shown that miRNAs associate with muscle loss in disease, including surgery, so may contribute to changes in gene expression. We analysed the change in muscle gene expression following surgery and compared it to pre‐ and postsurgical miRNA expression. We then analysed the effect of one of these miRNAs (miR‐675‐5p) on gene expression in myoblasts in the presence and absence of an inflammatory stimulus. Methods Differential gene expression analysis was performed on RNAseq data from rectus femoris biopsies (n = 18 male patients) pre‐ and postsurgery. Gene expression was compared with miRNA expression in the same samples to identify patterns of mRNA expression associated with physiology and miRNA expression. The effect of miR‐675‐5p on gene expression in the presence and absence of TNF‐α was determined in LHCN myoblasts by RNAseq. Results Postsurgery muscle had increased expression of gene sets associated with TNF‐α signalling (2.7‐fold) and MYC targets (2.7‐fold). Loss of muscle mass and strength associated with MYC target gene sets, but inflammatory gene sets only associated with loss of strength. Comparing miRNA expression with postsurgery gene expression showed that presurgery miR‐675‐5p expression was most closely associated with postsurgical gene expression, indicating that the presurgery phenotype is important in determining the response to surgery. Presurgery miR‐675‐5p correlated with change in gene expression in response to surgery (β = 1.30, p < 0.001), such that individuals with the highest presurgery miR‐675‐5p had the largest change in gene expression in response to surgery. In LHCN myoblasts miR‐675‐5p increased CCL2 protein release approximately 1.5‐fold (p < 0.001). RNAseq showed that, in the absence of TNF‐α, transfection with miR‐675‐5p increased the expression of 3422 genes with greatest enrichment of the hypoxia, myogenesis and TNF‐α signalling via NF‐κB gene sets. In the presence of TNF‐α, miR‐675‐5p increased the expression of 3403 genes, and the most enriched gene sets were the same suggesting that miR‐675‐5p increases the inflammatory response. miR‐675‐5p also increased the expression of MuRF1 in the presence and absence of TNF‐α. Conclusions Male patients with higher presurgical expression of miR‐675‐5p experienced a larger increase in inflammatory gene expression following surgery. MiR‐675‐5p increased inflammatory gene expression in myoblasts suggesting that it may contribute to the size of the inflammatory response.
ABSTRACT Background Musculoskeletal complications in type 2 diabetes (T2DM) are inadequately captured by body mass index (BMI). Waist‐to‐BMI ratio (WBR) may better reflect adverse body composition. We examined cross‐sectional and longitudinal associations between WBR and musculoskeletal disorders in T2DM. Methods This two‐phase study was conducted within an ongoing hospital‐based cohort at the First Affiliated Hospital of Fujian Medical University (Fuzhou, China). The cross‐sectional analysis included 4157 adults with T2DM recruited between March 2012 and August 2023 (54.3% men; mean age 59.4 ± 10.3 years), using data from their first assessment. Associations of waist circumference (WC), waist‐to‐height ratio (WHtR), waist‐to‐hip ratio (WHR), BMI and WBR with osteopenia, sarcopenia, sarcopenic osteopenia (SOs), sarcopenic obesity (SOb) and fractures were evaluated. The prospective cohort comprised a longitudinal subset enrolled between March 2012 and June 2022, ensuring at least 1 year of follow‐up prior to administrative censoring in August 2023. A total of 440 individuals (57.0% men; mean age 59.7 ± 9.7 years) were followed for a median of 34.0 months (20.0–57.0). Associations between time‐dependent WBR and incident outcomes were assessed using Cox models. A nested exploratory analysis was conducted within the cohort. Thirty participants with extreme annualised WBR change (ΔWBR/yr) were selected. Baseline serum samples collected at enrolment, prior to outcome occurrence, were analysed using phage immunoprecipitation sequencing (PhIP‐Seq). Results Cross‐sectionally, WBR was negatively correlated with bone mineral density and appendicular skeletal muscle mass index and positively correlated with osteopenia, sarcopenia, SOs, SOb and fractures (all p < 0.01), whereas BMI, WC, WHtR and WHR showed weaker associations. After adjustment, higher WBR was independently associated with osteopenia (men: OR 1.723, 95% CI 1.614–1.840; women: OR 1.420, 1.348–1.495), sarcopenia (men: OR 4.779, 4.165–5.484; women: OR 2.991, 2.683–3.334), SOs (men: OR 6.261, 5.314–7.377; women: OR 4.336, 3.753–5.010), SOb (men: OR 4.737, 3.975–5.646; women: OR 4.652, 3.715–5.825) and fractures (men: OR 1.236, 1.093–1.397; women: OR 1.103, 1.003–1.213; all p < 0.05). Prospectively, higher time‐dependent WBR predicted incident osteopenia (HR 1.365, 95% CI 1.024–1.820), sarcopenia (HR 1.282, 1.086–1.512), SOs (HR 1.408, 1.176–1.686), SOb (HR 1.634, 1.262–2.116) and fractures (HR 1.369, 1.029–1.821). PhIP‐Seq analysis identified differential autoantibody reactivity related to muscle structural organisation and cytoskeletal regulation, while bone‐related differences were enriched in Wnt signalling and hormone‐related pathways. Conclusions Higher WBR and longitudinal increases were independently associated with osteopenia, sarcopenia, sarcopenic phenotypes and fractures in individuals with T2DM.
ABSTRACT Background Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type–specific ECS changes in ALS. Methods Female hSOD1G93A transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56–138 days of age; n = 7–8/group). Endocannabinoids, N‐acyl‐ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC–MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS‐related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (n = 5/group; ~63 years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (n = 10–11/group), and survival, body weight, welfare and motor function were assessed longitudinally. Results ALS caused severe atrophy in the predominantly fast‐twitch TA muscle (−76.5%; p < 0.01), while the slow‐twitch soleus was largely preserved (−14.4%; p < 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy‐ and epoxy‐fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p = 0.03) and multiple N‐acyl‐ethanolamine congeners (+76–102%; p < 0.05), reduced 2‐arachidonoylglycerol (−28%; p = 0.06), increased CB1 receptor expression (+93%; p < 0.01) and dynamic, age‐dependent regulation of FAAH (presymptomatic: −68%; p = 0.04, symptomatic: +21%; p = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; pFDR = 0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all p > 0.05). Conclusions Muscle type–specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.
ABSTRACT Background Amputation is a critical event leading to the permanent loss of limb function and long‐term functional impairment, posing a substantial burden on global healthcare systems. However, the global burden, demographic patterns and future trajectory of amputation‐related disability have not been comprehensively quantified. Methods We analysed Global Burden of Disease (GBD) 2021 data to assess the prevalence and years lived with disability (YLDs) for seven amputation subtypes (fingers, thumbs, toes, unilateral and bilateral upper and lower limbs) from 1990 to 2021. Projections to 2050 were made using the Bayesian age–period–cohort (BAPC) modelling. Results In 2021, the global total number of amputation cases reached approximately 445 million (95% uncertainty intervals [UI]: 409–486 million), with an age‐standardized rate (ASR) of 5330 (95% UI: 4890–5820) cases per 100 000 population. From 1990 to 2021, the overall global burden of amputation demonstrated a declining trend in ASR, although the absolute number of cases increased substantially. Among all amputation subtypes, finger amputation (AMP‐F) had the highest prevalence, accounting for 50.3% of all cases, followed by thumb amputation (AMP‐Th) at 22.4% and toe amputation (AMP‐Toe) at 19.0%; these three subtypes alone accounted for over 91% of all cases. Regarding YLDs, unilateral lower limb amputation (AMP‐LL1) contributed most significantly (20.8%), followed by bilateral upper limb amputation (AMP‐UL2) at 18.9%, despite their relatively lower prevalence. In terms of the YLD burden, the age distribution exhibited a spindle‐shaped pattern, peaking in the 30–59 age group overall, with notable subtype‐specific variations (e.g., AMP‐LL1 peaking at ≥ 95 years and bilateral lower limb amputation [AMP‐LL2] prominent in middle‐aged groups, particularly 50–64 years in certain regions). Additionally, the etiological profile shifted markedly, with conflict and terrorism rising sharply from the 8th to the 4th leading driver of amputation burden globally, exerting a particularly strong impact in North Africa and the Middle East. Projections indicate substantial future increases in both prevalence and YLDs associated with AMP‐LL1, necessitating heightened vigilance. Conclusion Although the age‐standardized prevalence of amputation slightly declined globally from 1990 to 2021, the absolute number of cases increased significantly, exhibiting pronounced demographic and geographic disparities. To mitigate this escalating burden, tailored strategies integrating prevention and long‐term rehabilitation planning are urgently needed.
ABSTRACT Background The Skeletal Muscle Function Deficit (SMFD) score integrates muscle mass, strength, power and quality into a single construct that evaluates the multidimensional status of muscle health. The aim of the study is to investigate the longitudinal associations of systemic inflammation and caloric intake with SMFD‐score trajectories in older adults from the InCHIANTI study. Methods Data were obtained from the InCHIANTI population‐based longitudinal cohort. A total of 1035 community‐dwelling older adults (mean age 74.97 ± 7.39 years; 44.25% men) contributed 3196 repeated observations across four study waves. SMFD‐score (range 0–20) was derived from sex‐specific quintiles of lower‐limb muscle mass, muscle density, grip strength and lower‐limb power; participants unable to perform a test received a score of 0 for that component. Interleukin‐6 (IL‐6) and caloric intake (kcal/day) were assessed at all study waves. Longitudinal associations between time‐varying IL‐6 tertiles, caloric intake tertiles and SMFD‐score trajectories were evaluated using linear mixed‐effects models adjusted for baseline age and sex and time‐varying multimorbidity and body mass index. Results Across follow‐up, SMFD‐score declined significantly from 9.60 ± 4.20 at baseline to 7.07 ± 4.00 at the last wave (p < 0.001), whereas IL‐6 increased from 3.65 ± 2.50 pg/mL to 4.39 ± 3.10 pg/mL (p < 0.001). Mean caloric intake showed a non‐significant upward trend (1912.83 ± 562.37 to 1976.00 ± 580.54 kcal/day; p = 0.07). In mixed‐effects models, higher IL‐6 levels were associated with accelerated SMFD decline over time (IL‐6 tertile × time interaction β = −0.31 ± 0.02; p < 0.001). Higher caloric intake was associated with higher SMFD‐score and a slower functional decline (caloric intake tertile main effect β = 1.19 ± 0.16; p < 0.001; caloric intake tertile × time interaction β = 0.24 ± 0.03; p < 0.001). In the model including the combined IL‐6 × caloric intake × time interaction was statistically significant (β = 0.14 ± 0.04; p < 0.001), indicating that higher caloric intake partially attenuated the negative longitudinal association between IL‐6 and SMFD‐score. Conclusions SMFD‐score captures longitudinal muscle function decline during aging and reflects the opposing influences of inflammation and caloric intake. These findings support the SMFD‐score as a clinically relevant construct for identifying potentially modifiable determinants of muscle health and functional decline in older adults.
ABSTRACT Background Skeletal muscle atrophy is a frequent comorbidity of metabolic disorders and chronic diseases, and despite its high prevalence, no pharmacological therapy is available, representing a major unmet clinical need. Adiponectin and its receptors are key regulators of skeletal muscle metabolism, mitochondrial function and myogenesis, yet clinical translation has been hindered by the lack of receptor‐selective agonists with favourable pharmacological and safety profiles. Here, we report the identification and characterization of CDRI‐1709S, the first small‐molecule AdipoR1‐selective agonist and evaluate its myogenic and anti‐atrophy efficacy. Methods A PGC‐1α luciferase reporter‐based screen in AdipoR1/AdipoR2‐transfected, AdipoR‐low HEK293T cells identified CDRI‐1709S as an AdipoR1 agonist. Adiponectin‐associated signalling events were evaluated by immunoblotting in AdipoR1/2‐overexpressing HEK293T cells and AdipoR‐abundant C2C12 myotubes, with receptor specificity confirmed using RNA interference. Myogenic potential was assessed by morphometric analysis and immune detection of myogenic factors. Fibre‐type composition and metabolic capacity were evaluated using immunoblotting and extracellular flux analysis. Anti‐atrophy effects were examined in vitro using various assault‐induced models of myotube atrophy, and in vivo using rat models of dexamethasone (Dex) and sciatic nerve denervation‐induced muscle atrophy. Results CDRI‐1709S selectively activated AdipoR1 with high potency (EC50: 414.7pM) and, at a pharmacologically relevant concentration (100 nM), induced rapid adiponectin‐associated signalling, including phosphorylation of AMPK, AKT and p38‐MAPK, along with upregulation of its downstream skeletal muscle metabolic targets PGC‐1α, GLUT4 and UCP3 in an AdipoR1‐dependent manner (p < 0.05). CDRI‐1709S promoted C2C12 myoblast differentiation into mature myotubes, accompanied by increased expression of MyoD and myogenin (p < 0.05). Treated myotubes were protected against cytokine‐, Dex‐ and nutrient‐deprivation‐induced atrophy through suppression of atrogenes Atrogin‐1 and MuRF‐1 (p < 0.01), restoration of myogenic markers (p < 0.05) and prevention of Dex‐induced fibre‐type switching toward glycolytic MyHC‐IIB, with concomitant induction of slow (MyHC‐I) and fast (MyHC‐IIA) oxidative fibres (p < 0.05). CDRI‐1709S also reversed Dex‐mediated impairments in oxidative and glycolytic capacity (p < 0.05). Oral administration of CDRI‐1709S (10 mg/kg/day) in Dex‐ and denervation‐induced rat models restored atrogene expression, myogenic markers, local adiponectin signalling and myofibrillar architecture to normalcy (p < 0.05 to p < 0.0001). CDRI‐1709S prevented Dex‐induced enrichment of glycolytic fibres and preserved oxidative fibre composition (p < 0.05). The structural/molecular improvements translated into significant functional enhancements, including toe‐spread reflex in denervated limbs (p < 0.05) and increased grip strength (p < 0.0001) plus prolonged wire‐hang duration (p < 0.01) in Dex‐treated animals. Conclusion CDRI‐1709S is the first AdipoR1‐selective small‐molecule agonist that induced myogenesis and robustly ameliorated skeletal muscle atrophy, establishing the proof‐of‐concept for AdipoR1‐targeting as a promising therapeutic strategy for sarcopenia and skeletal muscle atrophy.
ABSTRACT Background Sarcopenia is characterized by progressive loss of muscle mass, strength and physical performance, yet current diagnostic tools are limited for practical and longitudinal monitoring. Extracellular vesicles (EVs) encapsulate various biomolecules, including proteins, nucleic acids, lipids and metabolites and have emerged as promising carriers of circulating biomarkers. In this study, we investigated longitudinal biomarkers of sarcopenia using plasma‐derived EVs. Methods Plasma EVs were isolated by density gradient ultracentrifugation from participants in the community‐based Korean Frailty and Aging Cohort Study (KFACS, n = 90) and performed quantitative proteomic profiling of EVs derived from plasma. Candidate proteins were validated in an independent hospital‐based Osteoporosis Sarcopenia (OsteoSarc, n = 93) cohort at Seoul National University Bundang Hospital using MRM‐based LC–MS/MS. Multivariate models were adjusted for age, sex, body mass index (BMI) and relevant covariates: metabolic comorbidities (hypertension, myocardial infarction, peripheral artery disease, cerebrovascular disease, and diabetes mellitus) in the KFACS cohort and femoral neck bone mineral density in the OsteoSarc cohort. Results In the KFACS cohort (mean age, 77.7 ± 4.1 years; range, 70.0–84.7; 50.0% women), EV‐associated complement proteins, particularly C2 and C4B, were strongly associated with declines in gait speed (β = −0.302, p = 0.006; β = −0.231, p = 0.028, respectively) and were elevated in individuals with worsened outcomes over 2 years (p = 0.002 and p = 0.034, respectively). Complement pathway enrichment analysis further supported associations with inflammatory and aging‐related signatures. Independent validation in the hospital‐based OsteoSarc cohort (mean age, 74.3 ± 12.0 years; range, 52.0–96.0; 88.2% women) confirmed the predictive value of C2 and C1R for gait speed and SPPB decline, with AUC values exceeding 0.7 for clinically relevant measures. Conclusion Our findings demonstrate that several EV‐associated complement proteins, including C2, C4B and C1R, are strongly associated with longitudinal decline in gait speed, highlighting their potential as promising circulating biomarkers for sarcopenia progression.
ABSTRACT Background Skeletal muscle dysfunction (SMD) is a common extrapulmonary complication of chronic obstructive pulmonary disease (COPD). Histone deacetylase 2 (HDAC2) is closely involved in the suppression of inflammatory transcription and is progressively reduced during COPD progression. Exosomes mediate intercellular communication by transferring bioactive cargos, including proteins. This study aimed to elucidate the molecular mechanism by which alveolar epithelial cell‐derived exosomes regulate HDAC2 and contribute to COPD‐related SMD. Methods Exosome inhibitor GW4869 was used to assess the role of exosomes in skeletal muscle injury induced by chronic cigarette smoke (CS) exposure. Exosomes isolated from the bronchoalveolar lavage fluid (BALF) of CS‐exposed mice and from cigarette smoke extract (CSE)‐exposed mouse alveolar epithelial (MLE12) cells were applied to recipient mice and/or mouse myoblast (C2C12) cells to evaluate muscle phenotypes, myogenic differentiation and cellular senescence. Rescue experiments using HDAC2 overexpression or HDAC activator ITSA1 treatment, together with proteomics and protein interaction assays, were performed to elucidate the underlying molecular mechanisms. Results GW4869 treatment ameliorated CS‐induced muscle dysfunction in mice, as evidenced by increased grip strength (222.4 ± 15.91 g vs. 159.2 ± 11.65 g, p < 0.001) and muscle fibre cross‐sectional area (404.0 ± 5.15 μm2 vs. 172.0 ± 5.39 μm2, p < 0.001), along with decreased muscle atrophy and senescence markers. In vitro, exosomes derived from 8% CSE‐exposed MLE12 cells (Exo‐CSE) impaired myogenic differentiation, decreased myotube diameter (10.50 ± 0.74 μm vs. 29.27 ± 0.48 μm, p < 0.001) and increased the number of senescent cells (206.7 ± 5.13 vs. 9.33 ± 1.53, p < 0.001). Exo‐CSE significantly reduced HDAC2 expression in C2C12 cells (0.18 ± 0.03 vs. 0.53 ± 0.04, p < 0.001), whereas HDAC2 overexpression or ITSA1 treatment rescued impaired myogenic differentiation and cellular senescence caused by Exo‐CSE. Proteomic analysis identified proline/arginine‐rich end leucine‐rich protein (PRELP) as a key exosomal cargo, and exosomes derived from PRELP‐silenced CSE‐exposed MLE12 cells markedly restored HDAC2 expression in recipient C2C12 cells (0.42 ± 0.02 vs. 0.18 ± 0.03, p < 0.001). Mechanistically, PRELP disrupted the stabilizing interaction between heat shock protein family A member 5 (HSPA5) and HDAC2, accelerating HDAC2 degradation, likely through the ubiquitin‐proteasome pathway. In vivo, the combination of PRELP knockdown and the HDAC activator ITSA1 synergistically alleviated CS‐induced muscle atrophy and senescence. Conclusions In COPD, CS‐exposed alveolar epithelial cells release PRELP‐enriched exosomes that promote SMD by disrupting HSPA5‐mediated HDAC2 stabilization and accelerating HDAC2 degradation. Targeting the PRELP‐HDAC2 axis may represent a potential therapeutic strategy for COPD‐related SMD.
ABSTRACT Background Electroacupuncture (EA) treatment has been utilized for recovery from neuromuscular‐related diseases and may play a significant role in the treatment of sarcopenia. This interventional, randomized controlled clinical study aims to explore the efficacy of EA treatment in maintenance haemodialysis (MHD) patients with sarcopenia. Methods Thirty‐six participants with sarcopenia undergoing MHD were randomly divided into the control group and the EA group. The participants in the EA group received a total of 24 treatments, each lasting 30 min, and were administered three times per week. Participants in the control group were instructed to continue their current lifestyle and treatment plans. The assessments were conducted at baseline and after 8 weeks. Statistical analysis was performed using two‐way analysis of covariance (ANCOVA) adjusted according to gender and baseline values. Repeated measures analysis of variance (ANOVA) was used to assess EA effects, reporting main effects and the time × group interaction with partial eta squared (η2p) effect sizes. The primary outcome was 6‐m gait speed; the secondary outcomes were skeletal muscle mass index (SMI) and handgrip strength. Fasting blood samples were collected, and serum metabolomics using the liquid chromatography–mass spectrometry method was employed to reveal metabolic changes. Results One participant from the EA group dropped out, and 35 participants were included in the analysis, aged (59.06 ± 11.69) years, including 22 men and 13 women. After intervention, the 6‐m gait speed of the EA group increased (Δ = 0.10 ± 0.08; p < 0.001), whereas that of the control group decreased (Δ = −0.06 ± 0.09; p = 0.018). The handgrip strength of the EA group increased (Δ = 0.68 ± 0.98; p = 0.011), whereas that of the control group decreased (Δ = −0.76 ± 1.19; p = 0.015). The SMI in the EA group increased (Δ = 0.19 ± 0.22; p = 0.003), although there was no significant difference in the control group. No serious adverse events were observed during the EA treatment. The results of serum metabolomics indicated that a total of 127 differentially expressed metabolites were identified (p < 0.05, VIP > 1), including 35 up‐regulated metabolites and 92 down‐regulated metabolites. KEGG pathway enrichment analysis showed that glycerophospholipid metabolism, linoleic acid metabolism and other pathways related to lipid metabolism were significantly changed. Conclusions EA treatment was an effective therapy for sarcopenia in patients undergoing MHD. Its therapeutic effect may be related to the positive regulation of systemic metabolism (including amino acid and lipid profiles).
ABSTRACT Background The health consequences of being underweight are less well‐studied than obesity. We aimed to examine the association between body mass index (BMI) and mortality from a wide range of diseases across the full BMI spectrum, with particular focus on how low BMI may affect premature and nonpremature death. Methods After excluding ever‐smokers and those with pre‐existing major diseases, this study included 262 704 women aged 30–79 from the China Kadoorie Biobank. The baseline BMI (kg/m2) was calculated using measured height and weight and classified into six groups: < 18.5, 18.5–19.9, 20.0–22.4, 22.5–23.9 (reference), 24.0–27.9 and ≥ 28.0. Long‐term follow‐up was conducted by linking to the local death registry. Cox regression was used to estimate the hazard ratios (HRs) of BMI with all‐cause and cause‐specific mortality, after adjusting for waist circumference and potential confounders. Results At baseline, 3.9%, 7.8% and 11.4% of participants had BMIs (kg/m2) of < 18.5, 18.5–19.9 and ≥ 28.0, respectively. During a median follow‐up of 17.1 years, 29 531 deaths were recorded, including 11 455 premature deaths (under the age of 70) and 18 076 nonpremature deaths. The risk of all‐cause mortality significantly increased at the lower extreme of BMI, reached a nadir around 23.5 kg/m2 estimated from restricted cubic splines and showed a modest increase at the upper extreme. Participants with BMI < 18.5, 18.5–19.9 and 20.0–22.4 had higher risks of premature death (HRs) of 1.91 (1.73–2.10), 1.24 (1.14–1.34) and 1.16 (1.11–1.21), respectively. The corresponding HRs for nonpremature death were 1.46 (1.36–1.56), 1.17 (1.10–1.23) and 1.04 (1.01–1.08). The analysis of premature death involved 33 diseases from eight ICD‐10 chapters, and nonpremature death involved 40 diseases from nine chapters. Underweight was linked to an increased risk of premature death in seven chapters and 10 diseases, including neoplasms (HR = 1.36, 95% CI: 1.16–1.59), endocrine‐metabolic (6.03, 4.13–8.82), circulatory (1.85, 1.56–2.20), respiratory (5.85, 3.89–8.80), digestive (5.64, 3.13–10.18), genitourinary (2.61, 1.20–5.69) and external causes (2.06, 1.55–2.72). Underweight was also associated with an increased risk of nonpremature death in four chapters and seven diseases. In contrast, obesity was only associated with increased risks of premature and nonpremature death in two and one chapters, respectively. Conclusion Among Chinese female healthy never‐smokers, underweight was an important risk factor for all‐cause and multiple cause‐specific mortality, especially the risk of premature death. While addressing the global obesity epidemic, the negative health consequences of low weight should not be ignored.
ABSTRACT Background Sarcopenia is a progressive skeletal muscle disorder prevalent in older adults, yet its role as a risk factor for acute postoperative cognitive decline—an early manifestation within the spectrum of perioperative neurocognitive disorders (PND)—remains underexplored. We hypothesize that preoperative sarcopenia increases the incidence of early postoperative cognitive impairment and adverse surgical outcomes in geriatric patients. Methods This prospective cohort study enrolled 443 older adult patients (mean age 72.8 ± 5.8 years, 58.3% male) undergoing elective noncardiac surgery at a single centre in China. Preoperative sarcopenia was diagnosed according to the 2019 Asian Working Group for Sarcopenia (AWGS) criteria, which included assessments of muscle mass, strength, and physical performance. Neurocognitive function was assessed via the Mini‐Mental State Examination (MMSE) 1 day before and 3 days after surgery, with acute cognitive decline defined as a postoperative decrease of ≥ 2 points. Of the 443 patients, 391 (88.2%) completed 6‐month telephone follow‐up for assessment of longer‐term functional outcomes. In an exploratory subset of 60 patients, preoperative faecal samples underwent 16S rRNA sequencing and untargeted metabolomics to characterize gut microbial and metabolic signatures. Results The prevalence of preoperative sarcopenia was 28.0% (124/443). Acute postoperative cognitive decline occurred in 27.3% (121/443) of patients. Multivariate logistic regression identified preoperative sarcopenia (adjusted OR = 3.291; 95% CI: 1.295–7.531; p < 0.001) and frailty (adjusted OR = 4.012; 95% CI: 1.854–8.456; p < 0.001) as independent risk factors for acute cognitive decline. Sarcopenic patients exhibited significantly higher rates of postoperative complications (adjusted RR = 1.21; 95% CI: 1.12–1.44; p = 0.025) and ICU admission (adjusted RR = 2.41; 95% CI: 1.03–4.41; p = 0.008). Among the 391 patients with complete 6‐month follow‐up, the sarcopenia group exhibited elevated risks of falls (adjusted RR = 2.89; 95% CI: 1.55–5.08; p = 0.028) and all‐cause mortality (adjusted RR = 3.07; 95% CI: 1.17–7.87; p = 0.016). Exploratory microbiome analysis revealed an elevated Firmicutes/Bacteroidetes ratio, reduced Bacteroides abundance, and upregulated faecal stercobilin and estradiol derivatives in sarcopenic patients who developed cognitive decline. Conclusion Preoperative sarcopenia is an independent risk factor for acute postoperative cognitive impairment and poor surgical outcomes in older adults. These findings support the integration of sarcopenia screening into preoperative risk stratification and suggest a potential role of the gut–muscle–brain axis in perioperative neurocognitive vulnerability.
