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Objective: Our objective was to investigate the overall and sex‐specific relationships between the presence and severity of knee osteoarthritis (KOA) and muscle composition, power, and energetics in older adults. Methods: Male and female patients (n = 655, mean ± SD age 76.1 ± 4.9 years; 57% female) enrolled in the Study of Muscle, Mobility, and Aging completed standing knee radiographs and knee pain assessments. Participants were divided into three groups using Kellgren‐Lawrence grade (KLG) of KOA severity (0–1, 2, or 3–4). Outcome measures included whole‐body muscle mass, thigh fat‐free muscle (FFM) volume and muscle fat infiltration (MFI), leg power, specific power (power normalized to muscle volume), and muscle mitochondrial energetics. Results: Overall, the presence and severity of KOA is associated with greater MFI, lower leg power and specific power, and reduced oxidative phosphorylation (P trend < 0.036). Sex‐specific analysis revealed reduced energetics only in female patients with KOA (P trend < 0.007) compared to female patients without KOA. In models adjusted for age, sex, race, nonsteroidal anti‐inflammatory drug administration, site or technician, physical activity, height, and participants with abdominal adiposity with KLG 3 to 4 had greater MFI (mean 0.008%, 95% confidence interval [CI] 0.004%–0.011%) and lower leg power (mean −51.56 W, 95% CI −74.03 to −29.10 W) and specific power (mean −5.38 W/L, 95% CI −7.31 to −3.45 W/L) than those with KLG 0 to 1. No interactions were found between pain and KLG status. Among those with KOA, MFI and oxidative phosphorylation were associated with thigh FFM volume, leg power, and specific power. Conclusion: Muscle health is associated with the presence and severity of KOA and differs by sex. Although muscle composition and power are lower in both male and female patients with KOA, regardless of pain status, mitochondrial energetics is reduced only in female patients. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (OA), characterized by multiple joint tissue degenerations, remains a significant clinical challenge. Recent evidence suggests that crosstalk within the osteochondral unit may drive OA progression. Although structural-biomechanical properties of bone and cartilage have been studied, potential interaction within the osteochondral unit in the context of OA has yet to be investigated. We performed comprehensive structural and biomechanical quantification of the cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) using 101 osteochondral cores collected from tibial plateaus of 12 control human cadavers (CT, 5 male/7 female) and 19 patients undergoing total knee replacement (OA, 6 male/13 female). For each sample, we quantified SBP microstructure, plate-and-rod morphological properties of the STB using individual trabecula segmentation, and morphological and compositional properties of the articular cartilage. We also performed indentation testing on each compartment of the osteochondral unit to extract the respective structural-mechanical properties. Cartilage thickness was lower in moderate and severe OA regions, while Osteoarthritis Research Society International score was higher only in severe OA regions. GAG content did not change in any OA region. Aggregate and shear moduli were lower only in severe OA regions, while permeability was lower only in moderate OA regions. In the SBP, thickness and tissue mineral density were higher in moderate and severe OA regions. Tissue modulus of STB was lower in moderate OA regions despite a thicker and more mineralized SBP; this deterioration was not observed in severe OA regions. Regression analysis revealed strong correlations between cartilage and STB properties in CT; these correlations were also found in moderate OA regions but were not observed in severe OA regions. In summary, our findings comprehensively characterize the human OA osteochondral unit. Importantly, uncoupling cartilage and subchondral bone structural-mechanical properties may be a hallmark of OA. Lay Summary: Knee osteoarthritis (OA) is a complex condition involving the degradation of joint tissues. To better understand OA progression, we investigated the interplay between different components of the joint. Our study focused on how cartilage, subchondral bone plate (SBP), and subchondral trabecular bone (STB) interact in human knee OA samples. We observed distinct changes in these tissues in moderate and severe OA regions compared with healthy joints. In moderate to severe OA, we found that cartilage thickness decreased, while the SBP thickened. Interestingly, the strength of the STB decreased only in moderate OA regions, not in severe OA. Moreover, our analysis revealed strong correlations between cartilage and STB properties in healthy joints and moderate OA regions. However, these correlations were absent in severe OA regions, indicating a disruption in the usual relationship between these tissues. Overall, our findings shed light on the structural and biomechanical changes occurring within the knee joint in OA. Understanding these changes may offer insights into potential therapeutic strategies for managing OA. [ABSTRACT FROM AUTHOR]

Tryptophan (TRP) metabolites along the kynurenine (KYN) pathway (KP) have been found to influence muscle. Proinflammatory cytokines are known to stimulate the degradation of TRP down the KP. Given that both inflammation and KP metabolites have been connected with loss of muscle, we assessed the potential mediating role of KP metabolites on inflammation and muscle mass in older men. Five hundred and five men (85.0 ± 4.2 years) from the Osteoporotic Fractures in Men cohort study with measured D3-creatine dilution (D3Cr) muscle mass, KP metabolites, and inflammation markers (C-reactive protein [CRP], alpha-1-acid glycoprotein [AGP] and a subsample [ n  = 305] with interleukin [IL-6, IL-1β, IL-17A] and tumor necrosis factor-α [TNF-α]) were included in the analysis. KP metabolites and inflammatory markers were measured using liquid chromatography-tandem mass spectrometry and immunoassays, respectively. 23%–92% of the inverse relationship between inflammatory markers and D3Cr muscle mass was mediated by KP metabolites (indirect effect p  < .05). 3-hydroxyanthranilic acid (3-HAA), quinolinic acid (QA), TRP, xanthurenic acid (XA), KYN/TRP, 3-hydroxykynurenine (3-HK)/3-HAA, QA/3-HAA, and nicotinamide (NAM)/QA mediated the AGP relationship. 3-HAA, QA, KYN/TRP, 3-HK/XA, HKr ratio, 3-HK/3-HAA, QA/3-HAA, and NAM/QA mediated the CRP. KYN/TRP, 3-HK/XA, and NAM/QA explained the relationship for IL-6 and 3-HK/XA and QA/3-HAA for TNF-α. No mediation effect was observed for the other cytokines (indirect effect p  > .05). KP metabolites, particularly higher ratios of KYN/TRP, 3-HK/XA, 3-HK/3-HAA, QA/3-HAA, and a lower ratio of NAM/QA, mediated the relationship between inflammation and low muscle mass. Our preliminary cross-sectional data suggest that interventions to alter D3Cr muscle mass may focus on KP metabolites rather than inflammation per se. [ABSTRACT FROM AUTHOR]

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation‐responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation‐responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation‐responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age. [ABSTRACT FROM AUTHOR]

Background The effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community-dwelling older adults both overall, and in relation, to sociodemographic characteristics. Methods We examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N  = 820, age = 76.4 years, 58.2% women) participating in the Study of Muscle, Mobility, and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance. Results Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR versus men (all p  < .05). Total activity (56%) and time of activity (20%) accounted for most of the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (p  < .001). Compared to the latest decile of acrophase, those in the earliest and midrange categories had more total activity (p  = .02). Being in a married-like relationship and a more stable financial situation were associated with stronger rhythms; higher education was associated with less rhythm strength (all p  < .05). Conclusions Older age was associated with dampened circadian behavior; behaviors were sexually dimorphic. Some sociodemographic characteristics were associated with circadian behavior. We identified a behavioral phenotype characterized by early time of day of peak activity, high rhythmic amplitude, and more total activity. [ABSTRACT FROM AUTHOR]

Background Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70–94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. Results At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p <.001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p =.054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p <.05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p =.008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p =.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02–1.73, p =.033). However, covariates accounted for the increased risk. Conclusions Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway. [ABSTRACT FROM AUTHOR]

Objective: The current guidelines recommend weight loss for patients with overweight or obesity and knee or hip osteoarthritis (OA); however, there is a paucity of data on the relation of weight loss to death among patients with OA. We aimed to examine the relation of the rate of weight loss induced by antiobesity medications over one year to all‐cause mortality among patients with overweight or obesity and knee or hip OA. Methods: Using the IQVIA Medical Research Database, we identified people with overweight or obesity and knee or hip OA. We emulated analyses of a hypothetical target trial to assess the effect of slow‐to‐moderate (2%–10%) or fast (≥10%) weight loss induced by the initiation of antiobesity medications within one year on all‐cause mortality and secondary outcomes over five years' follow‐up. Results: Among 6,524 participants, the five‐year all‐cause mortality rates were 5.3%, 4.0%, and 5.4% for weight gain or stable, slow‐to‐moderate weight loss, and fast weight loss arms, respectively. Compared with the weight gain or stable arm, hazard ratios of all‐cause mortality were 0.72 (95% confidence interval [CI] 0.56–0.92) for the slow‐to‐moderate weight loss arm and 0.99 (95% CI 0.67–1.44) for the fast weight loss arm. We found dose–response protective effects of weight loss on incident hypertension, type 2 diabetes, and venous thromboembolism but a slightly higher risk of cardiovascular disease, albeit not statistically significant, in the fast rate of weight loss arm than in the weight gain or stable arm and no significant relations of weight loss to the risk of cancer. Conclusion: In this population‐based study, a slow‐to‐moderate, but not fast, rate of weight loss induced by antiobesity medications is associated with a lower risk of all‐cause mortality in people with overweight or obesity and knee or hip OA. [ABSTRACT FROM AUTHOR]