Fracture discrimination capability of ulnar flexural rigidity measured via Cortical Bone Mechanics Technology: study protocol for The STRONGER Study.

Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, which leads to bone fragility (ie, weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is DXA, which quantifies areal BMD, typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating the bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicate that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: Better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).

Age-related dysregulation of the retinal transcriptome in African turquoise killifish.

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNAseq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in the ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterized, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNAseq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasizes the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.

Effects of a ketogenic diet on motor function and motor unit number estimation in aged C57BL/6 mice.

OBJECTIVE: Pathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice. DESIGN: A randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention. SETTING: Preclinical laboratory study. SAMPLE SIZE: Thirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)]. MEASUREMENTS: Measures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, muscle wet weight and blood samples were collected to assess blood beta-hydroxybutyrate levels. STATISTICAL ANALYSIS: Primary analyses were two-way mixed effects ANOVA (diet and time × diet) to determine the effect of a KD on indices of motor function (grip, rotarod) and indices of motor unit (MUNE) and muscle (contractility) function. RESULTS: Beta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (diet, p = 0.0001; time × diet, p = 0.0030), all limb grip strength (diet, p = 0.0005; time × diet, p = 0.0523), and rotarod latency to fall (diet, p = 0.0126; time × diet, p = 0.0021). Mice treated with the KD intervention also demonstrated increased MUNE (diet, p = 0.0465; time × diet, p = 0.0064), but no difference in muscle contractility (diet, p = 0.5248; time × diet, p = 0.5836) or RNS (diet, p = 0.3562; time × diet, p = 0.9871). CONCLUSION: KD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

Age-related dysregulation of the retinal transcriptome in African turquoise killifish.

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.

Assessing muscular power in older adults: evaluating the predictive capacity of the 30-second chair rise test.

Background: Timed chair rise tests are frequently used as a substitute for assessing leg muscle strength or power. To determine if timed chair rise tests are an indicator of lower extremity muscle power, we examined the relationship between the repetitions completed in a 30-s chair rise test and the power generated during the test. Methods: Seventy-five individuals participated in this study (n = 30 < 65 years and 45 ≥ 65 years). Participants underwent a 30-s chair rise test while instrumented with a power analyzer. Handgrip strength was also evaluated. Results: The relationship between chair rise repetitions and average chair rise power was R 2 = 0.32 (p < 0.001). Chair rise repetitions when regressed on a total (i.e., summed) chair rise power, it yielded R 2 = 0.70 with data from all participants combined (p < 0.001). A mediation analysis indicated that anthropometrics partially mediates the relationship between chair rise repetitions and total chair rise power accounting for 2.8%-6.9% of the variance. Conclusion: Our findings indicate that in older adults, the overall performance of chair rises offers limited information about the average power per rise but is more indicative of the cumulative power exerted. Thus, the total number of chair rises in a 30-s test is likely a more comprehensive metric of overall muscular power, reflecting endurance aspects as well. Additionally, we found that personal physical attributes, such as height and weight, partially influence the link between chair rise count and total power, highlighting the importance of factoring in individual body metrics in assessments of muscular performance.

Lumbar Spine Anatomy in Supine versus Weight- Bearing Magnetic Resonance Imaging: Detecting Significant Positional Changes and Testing Reliability of Quantification.

STUDY DESIGN: Testing between and within group differences and assessing reliability of measurements. PURPOSE: To study and compare lumbar spine morphology in supine and weight-bearing (WB) magnetic resonance imaging (MRI). OVERVIEW OF LITERATURE: Upright lumbar MRI may uncover anatomical changes that may escape detection when using conventional supine imaging. This study quantified anatomical dimensions of the lumbar spine in the supine and WB MRI, compared specific morphometric differences between them, and tested the intra-rater reliability of the measurements. Repeated measures analysis was used to compare within- and between-session measurements performed on the supine and WB images. Reliability and agreement were assessed by calculating intraclass correlation (ICC) coefficient. METHODS: Data from 12 adults without any history of back pain were used in this study. Sagittal T2-weighted images of the lumbar spine were acquired in the supine and WB positions twice (in two separate sessions scheduled within a week). Linear, angular dimensions, and cross-sectional areas (CSAs) were measured using proprietary software. Supine and WB data acquired from the two imaging sessions were tested for intra-rater reliability. Quantified data were normalized for each session to test the significance of differences. ICC was calculated to test the reliability of the measurements. RESULTS: Linear, angular, and CSA measurements demonstrated strong within-position (supine and WB) correlations (r -values, 0.75-0.97). Between-position (supine vs. WB) differences were significant for all measured dimensions (p<0.05). Between-session measurements demonstrated a strong correlation (r -values, 0.64-0.83). Calculated ICC showed strong agreement among the measurements. CONCLUSIONS: Anatomical dimensions of the lumbar spine may demonstrate consistent and significant differences between supine and WB MRI for specific structural parameters.

Reductions in Motor Unit Firing are Associated with Clinically Meaningful Leg Extensor Weakness in Older Adults.

Weakness, one of the key characteristics of sarcopenia, is a significant risk factor for functional limitations and disability in older adults. It has long been suspected that reductions in motor unit firing rates (MUFRs) are one of the mechanistic causes of age-related weakness. However, prior work has not investigated the extent to which MUFR is associated with clinically meaningful weakness in older adults. Forty-three community-dwelling older adults (mean: 75.4 ± 7.4 years; 46.5% female) and 24 young adults (mean: 22.0 ± 1.8 years; 58.3% female) performed torque matching tasks at varying submaximal intensities with their non-dominant leg extensors. Decomposed surface electromyographic recordings were used to quantify MUFRs from the vastus lateralis muscle. Computational modeling was subsequently used to independently predict how slowed MUFRs would negatively impact strength in older adults. Bivariate correlations between MUFRs and indices of lean mass, voluntary activation, and physical function/mobility were also assessed in older adults. Weak older adults (n = 14) exhibited an approximate 1.5 and 3 Hz reduction in MUFR relative to non-weak older adults (n = 29) at 50% and 80% MVC, respectively. Older adults also exhibited an approximate 3 Hz reduction in MUFR relative to young adults at 80% MVC only. Our model predicted that a 3 Hz reduction in MUFR results in a strength decrement of 11-26%. Additionally, significant correlations were found between slower MUFRs and poorer neuromuscular quality, voluntary activation, chair rise time performance, and stair climb power (r's = 0.31 to 0.43). These findings provide evidence that slowed MUFRs are mechanistically linked with clinically meaningful leg extensor weakness in older adults.

Comparison of strategies for assessment of rate of torque development in older and younger adults.

There is increasing appreciation of the role of rate of torque development (RTD) in physical function of older adults (OAs). This study compared various RTD strategies and electromyography (EMG) in the knee extensors and focused on discriminating groups with potential limitations in voluntary activation (VA) and associations of different RTD indices with functional tests that may be affected by VA in OAs. Neuromuscular function was assessed in 20 younger adults (YAs, 22.0 ± 1.7 years) and 50 OAs (74.4 ± 7.0 years). Isometric ballistic and peak torque during maximal voluntary contractions (pkTMVC), doublet stimulation and surface EMG were assessed and used to calculate VA during pkTMVC and RTD and rate of EMG rise during ballistic contractions. Select mobility tests (e.g., gait speed, 5× chair rise) were also assessed in the OAs. Voluntary RTD and RTD normalized to pkTMVC, doublet torque, and peak doublet RTD were compared. Rate of EMG rise and voluntary RTD normalized to pkTMVC did not differ between OAs and YAs, nor were they associated with functional test scores. Voluntary RTD indices normalized to stimulated torque parameters were significantly associated with VA (r = 0.319-0.459), and both indices were significantly lower in OAs vs YAs (all p < 0.020). These RTD indices showed significant association with the majority of mobility tests, but there was no clear advantage among them. Thus, voluntary RTD normalized to pkTMVC was ill-suited for use in OAs, while results suggests that voluntary RTD normalized to stimulated torque parameters may be useful for identifying central mechanisms of RTD impairment in OAs.Clinical trial registration number NCT02505529; date of registration 07/22/2015.

Ketogenic Diet Improves Motor Function and Motor Unit Connectivity in Aged C57BL/6 Mice.

Objective: Pathological, age-related loss of muscle function, commonly referred to as sarcopenia, contributes to loss of mobility, impaired independence, as well as increased risk of adverse health events. Sarcopenia has been attributed to changes in both neural and muscular integrity during aging. Current treatment options are primarily limited to exercise and dietary protein fortification, but the therapeutic impact of these approaches are often inadequate. Prior work has suggested that a ketogenic diet (KD) might improve healthspan and lifespan in aging mice. Thus, we sought to investigate the effects of a KD on neuromuscular indices of sarcopenia in aged C57BL/6 mice. Design: A randomized, controlled pre-clinical experiment consisting of longitudinal assessments performed starting at 22-months of age (baseline) as well as 2, 6 and 10 weeks after the start of a KD vs. regular chow intervention. Setting: Preclinical laboratory study. Sample size: Thirty-six 22-month-old mice were randomized into 2 dietary groups: KD [n = 22 (13 female and 9 male)], and regular chow [n = 15 (7 female and 8 male)]. Measurements: Measures included body mass, hindlimb and all limb grip strength, rotarod for motor performance, plantarflexion muscle contractility, motor unit number estimations (MUNE), and repetitive nerve stimulation (RNS) as an index of neuromuscular junction transmission efficacy recorded from the gastrocnemius muscle. At end point, blood samples were collected to assess blood beta-hydroxybutyrate levels. Statistical Analysis: Two-way ANOVA mixed-effects analysis (time x diet) were performed to analyze grip, rotarod, MUNE, and muscle contractility data. Results: Beta-hydroxybutyrate (BHB) was significantly higher at 10 weeks in mice on a KD vs control group (0.83 ± 0.44 mmol/l versus 0.42 ± 0.21 mmol/l, η2 = 0.265, unpaired t-test, p = 0.0060). Mice on the KD intervention demonstrated significantly increased hindlimb grip strength (time x diet, p = 0.0030), all limb grip strength (time x diet, p = 0.0523), and rotarod latency to fall (time x diet, p = 0.0021). Mice treated with the KD intervention also demonstrated significantly greater MUNE (time x diet, p = 0.0064), but no difference in muscle contractility (time x diet, p = 0.5836) or RNS (time x diet, p = 0.9871). Conclusion: KD intervention improved neuromuscular and motor function in aged mice. This pre-clinical work suggests that further research is needed to assess the efficacy and physiological effects of a KD on indices of sarcopenia.

The relation of ApoE and COMT gene-gene interactions to cognitive and motor function in community-dwelling older adults: a pilot study.

Introduction: Certain genes increase the risk of age-related neurological dysfunction and/or disease. For instance, ApoE is a well-known gene carrying risk for Alzheimer's disease, while COMT has been associated with age-related reductions in motor function. There is growing interest in the interrelationship between age-related changes in cognitive and motor function, and examining gene-gene interactions in this context. In this pilot study we examined the relations of the ApoE and COMT genes and their interaction to both cognitive and motor performance in community-dwelling older adults. Methods: We leveraged an archived dataset from a prior study on age-related muscle weakness in community-dwelling older adults. Sample size was between 72 and 82 individuals based on missing data. We examined the relationship of ApoE (Ɛ4 presence/absence), rs4680 SNP on the COMT gene (Val/Met, Val/Val, Met/Met), and sex on (1) overall cognitive functioning and specific cognitive domains known to decline in aging (processing speed, immediate and delayed memory, semantic and phonemic fluency, and executive functioning), and (2) indices of motor function (four square step test, short physical performance battery, grip strength/forearm lean mass, and purdue pegboard test). Results: Homozygous COMT genotypes were associated with worse global cognitive performance, immediate memory, and semantic fluency, but only for older adults with at least one ApoE Ɛ4 allele. There were main effects for COMT for delayed memory and a main effect for both COMT and ApoE for coding and phonemic fluency. Women scored higher than men in overall cognition, immediate and delayed memory, and semantic fluency. There were no main effects or gene interactions for a measure of executive functioning (trial making test part B) or any of the measures of motor function. Discussion: COMT, ApoE, and their interaction influence cognitive performance, but not motor functioning, in community dwelling older adults. Our work supports prior literature concluding that a heterozygous COMT genotype may be beneficial to sustain healthy cognitive functioning with advancing age for those who have a higher ApoE genetic risk status (at least one Ɛ4 allele). Future research should investigate interactions between COMT and ApoE in larger samples with comprehensive assessment of cognition and motor functioning.

Removing acoustic ringing baseline curvature in 13 C NMR spectra for quantitative analyses.

13 C nuclear magnetic resonance (NMR) is traditionally considered an insensitive technique, requiring long acquisition times to measure dilute functionalities on large polymers. With the introduction of cryoprobes and better electronics, sensitivity has improved in a way that allows measurements to take less than 1/20th the time that they previously did. Unfortunately, a high Q-factor with cryoprobes creates baseline curvature related to acoustic ringing that affects quantitative NMR analyses. Manual baseline correction is commonly used to compensate for the baseline roll, but it is a time-intensive process. The outcome of manual baseline correction can vary depending on processing parameters, especially for complicated spectra. Additionally, it can be challenging to distinguish between broad peaks and baseline rolls. A new anti-ring pulse sequence (zgig_pisp) was previously reported to improve on the incumbent single pulse experiment (zgig). The original report presented limited comparison data with 13 C NMR, but a thorough validation is needed before broader implementation can be considered. In this work, we report the round-robin testing and comparison of zgig_pisp and zgig pulse sequences. During the testing phase, we found that zgig_pisp is practically equivalent to zgig to ±2% for the majority of integrals examined. Additionally, a short broadband inversion pulse (BIP) was demonstrated as an alternative to the originally reported adiabatic CHIRP shaped pulse. The zgig_pisp pulse sequence code for Bruker spectrometers is also simplified.

Prevalence and Trends of Handgrip Strength Asymmetry in the United States.

Background: Strength asymmetries are a type of muscle function impairment that is associated with several health conditions. However, the prevalence of these asymmetries among adults from the United States remains unknown. We sought to estimate the prevalence and trends of handgrip strength (HGS) asymmetry in American adults. Methods: The unweighted analytic sample included 23,056 persons aged at least 50-years with information on HGS for both hands from the 2006-2016 waves of the Health and Retirement Study. A handgrip dynamometer measured HGS, with the highest recorded values for each hand used to calculate asymmetry. Persons were categorized into the following asymmetry severity categories: (1) >10%, (2) >20.0%, and (3) >30.0%. Survey weights were used to generate nationally-representative asymmetry estimates. Results: Overall, there were no statistically significant trends in HGS asymmetry categories over time. The prevalence of HGS asymmetry in the 2014-2016 wave was 53.4% (CI: 52.2-54.4), 26.0% (CI: 25.0-26.9), and 11.7% (CI: 10.9-12.3) for asymmetry at >10%, >20%, and >30%, respectively. HGS asymmetry was generally higher in older Americans compared to middle-aged adults at each wave. In the 2014-2016 wave, >30% asymmetry prevalence was 13.7% (CI: 12.7-14.6) in females and 9.3% (CI: 8.4-10.2) in males. Some differences in asymmetry prevalence by race and ethnicity were observed. Conclusions: The prevalence of asymmetry was generally high, especially in women and older adults. Ongoing surveillance of strength asymmetry will help monitor trends in muscle dysfunction, guide screening for disablement, identify subpopulations at risk for asymmetry, and inform relevant interventions.

Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.

BACKGROUND: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19). OBJECTIVE: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease. METHODS: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality. RESULTS: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/µL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well. CONCLUSIONS: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation.

Neuromuscular junction transmission failure in aging and sarcopenia: The nexus of the neurological and muscular systems.

Sarcopenia, or age-related decline in muscle form and function, exerts high personal, societal, and economic burdens when untreated. Integrity and function of the neuromuscular junction (NMJ), as the nexus between the nervous and muscular systems, is critical for input and dependable neural control of muscle force generation. As such, the NMJ has long been a site of keen interest in the context of skeletal muscle function deficits during aging and in the context of sarcopenia. Historically, changes of NMJ morphology during aging have been investigated extensively but primarily in aged rodent models. Aged rodents have consistently shown features of NMJ endplate fragmentation and denervation. Yet, the presence of NMJ changes in older humans remains controversial, and conflicting findings have been reported. This review article describes the physiological processes involved in NMJ transmission, discusses the evidence that supports NMJ transmission failure as a possible contributor to sarcopenia, and speculates on the potential of targeting these defects for therapeutic development. The technical approaches that are available for assessment of NMJ transmission, whether each approach has been applied in the context of aging and sarcopenia, and the associated findings are summarized. Like morphological studies, age-related NMJ transmission deficits have primarily been studied in rodents. In preclinical studies, isolated synaptic electrophysiology recordings of endplate currents or potentials have been mostly used, and paradoxically, have shown enhancement, rather than failure, with aging. Yet, in vivo assessment of single muscle fiber action potential generation using single fiber electromyography and nerve-stimulated muscle force measurements show evidence of NMJ failure in aged mice and rats. Together these findings suggest that endplate response enhancement may be a compensatory response to post-synaptic mechanisms of NMJ transmission failure in aged rodents. Possible, but underexplored, mechanisms of this failure are discussed including the simplification of post-synaptic folding and altered voltage-gated sodium channel clustering or function. In humans, there is limited clinical data that has selectively investigated single synaptic function in the context of aging. If sarcopenic older adults turn out to exhibit notable impairments in NMJ transmission (this has yet to be examined but based on available evidence appears to be plausible) then these NMJ transmission defects present a well-defined biological mechanism and offer a well-defined pathway for clinical implementation. Investigation of small molecules that are currently available clinically or being testing clinically in other disorders may provide a rapid route for development of interventions for older adults impacted by sarcopenia.

Brain activity associated with quadriceps strength deficits after anterior cruciate ligament reconstruction.

Prolonged treatment resistant quadriceps weakness after anterior cruciate ligament reconstruction (ACL-R) contributes to re-injury risk, poor patient outcomes, and earlier development of osteoarthritis. The origin of post-injury weakness is in part neurological in nature, but it is unknown whether regional brain activity is related to clinical metrics of quadriceps weakness. Thus, the purpose of this investigation was to better understand the neural contributions to quadriceps weakness after injury by evaluating the relationship between brain activity for a quadriceps-dominated knee task (repeated cycles of unilateral knee flexion/extension from 45° to 0°), , and strength asymmetry in individuals returned to activity after ACL-R. Forty-four participants were recruited (22 with unilateral ACL reconstruction; 22 controls) and peak isokinetic knee extensor torque was assessed at 60°/s to calculate quadriceps limb symmetry index (Q-LSI, ratio of involved/uninvolved limb). Correlations were used to determine the relationship of mean % signal change within key sensorimotor brain regions and Q-LSI. Brain activity was also evaluated group wise based on clinical recommendations for strength (Q-LSI < 90%, n = 12; Q-LSI ≥ 90%, n = 10; controls, all n = 22 Q-LSI ≥ 90%). Lower Q-LSI was related to increased activity in the contralateral premotor cortex and lingual gyrus (p < .05). Those who did not meet clinical recommendations for strength demonstrated greater lingual gyrus activity compared to those who met clinical recommendations Q-LSI ≥ 90 and healthy controls (p < 0.05). Asymmetrically weak ACL-R patients displayed greater cortical activity than patients with no underlying asymmetry and healthy controls.

Neural Mechanisms of Age-Related Loss of Muscle Performance and Physical Function.

BACKGROUND: This article discusses the putative neural mechanisms of age-related muscle weakness within the broader context of the development of function-promoting therapies for sarcopenia and age-related mobility limitations. We discuss here the evolving definition of sarcopenia and its primary defining characteristic, weakness. METHODS: This review explores the premise that impairments in the nervous system's ability to generate maximal force or power contribute to sarcopenia. RESULTS: Impairments in neural activation are responsible for a substantial amount of age-related weakness. The neurophysiological mechanisms of weakness are multifactorial. The roles of supraspinal descending command mechanisms, spinal motor neuron firing responsivity, and neuromuscular junction transmission failure in sarcopenia are discussed. Research/clinical gaps and recommendations for future work are highlighted. CONCLUSION: Further research is needed to map putative neural mechanisms, determine the clinical relevance of age-related changes in neural activation to sarcopenia, and evaluate the effectiveness of various neurotherapeutic approaches to enhancing physical function.

Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis.

Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise "adaptive regeneration." We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.

Age-related changes in gait biomechanics and their impact on the metabolic cost of walking: Report from a National Institute on Aging workshop.

Changes in old age that contribute to the complex issue of an increased metabolic cost of walking (mass-specific energy cost per unit distance traveled) in older adults appear to center at least in part on changes in gait biomechanics. However, age-related changes in energy metabolism, neuromuscular function and connective tissue properties also likely contribute to this problem, of which the consequences are poor mobility and increased risk of inactivity-related disease and disability. The U.S. National Institute on Aging convened a workshop in September 2021 with an interdisciplinary group of scientists to address the gaps in research related to the mechanisms and consequences of changes in mobility in old age. The goal of the workshop was to identify promising ways to move the field forward toward improving gait performance, decreasing energy cost, and enhancing mobility for older adults. This report summarizes the workshop and brings multidisciplinary insight into the known and potential causes and consequences of age-related changes in gait biomechanics. We highlight how gait mechanics and energy cost change with aging, the potential neuromuscular mechanisms and role of connective tissue in these changes, and cutting-edge interventions and technologies that may be used to measure and improve gait and mobility in older adults. Key gaps in the literature that warrant targeted research in the future are identified and discussed.