Dataset Information

Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice.

ABSTRACT: Loss of bone and muscle mass are two major clinical complications among the growing list of chronic diseases that primarily affect elderly individuals. Persistent low-grade inflammation, one of the major drivers of aging, is also associated with both bone and muscle dysfunction in aging. Particularly, chronic activation of the receptor for advanced glycation end products (RAGE) and elevated levels of its ligands high mobility group box 1 (HMGB1), AGEs, S100 proteins and A? fibrils have been linked to bone and muscle loss in various pathologies. Further, genetic or pharmacologic RAGE inhibition has been shown to preserve both bone and muscle mass. However, whether short-term pharmacologic RAGE inhibition can prevent early bone and muscle loss in aging is unknown. To address this question, we treated young (4-mo) and middle-aged (15-mo) C57BL/6 female mice with vehicle or Azeliragon, a small-molecule RAGE inhibitor initially developed to treat Alzheimer's disease. Azeliragon did not prevent the aging-induced alterations in bone geometry or mechanics, likely due to its differential effects [direct vs. indirect] on bone cell viability/function. On the other hand, Azeliragon attenuated the aging-related body composition changes [fat and lean mass] and reversed the skeletal muscle alterations induced with aging. Interestingly, while Azeliragon induced similar metabolic changes in bone and skeletal muscle, aging differentially altered the expression of genes associated with glucose uptake/metabolism in these two tissues, highlighting a potential explanation for the differential effects of Azeliragon on bone and skeletal muscle in middle-aged mice. Overall, our findings suggest that while short-term pharmacologic RAGE inhibition did not protect against early aging-induced bone alterations, it prevented against the early effects of aging in skeletal muscle.

SUBMITTER: Davis HM

PROVIDER: S-EPMC6543548 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice.

Davis Hannah M HM Essex Alyson L AL Valdez Sinai S Deosthale Padmini J PJ Aref Mohammad W MW Allen Matthew R MR Bonetto Andrea A Plotkin Lilian I LI

Bone 20190424

Loss of bone and muscle mass are two major clinical complications among the growing list of chronic diseases that primarily affect elderly individuals. Persistent low-grade inflammation, one of the major drivers of aging, is also associated with both bone and muscle dysfunction in aging. Particularly, chronic activation of the receptor for advanced glycation end products (RAGE) and elevated levels of its ligands high mobility group box 1 (HMGB1), AGEs, S100 proteins and Aβ fibrils have been link ...[more]

PMID: 31028960

Similar Datasets

Project description:Background:Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. Methods:We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Results:Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Conclusions:Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions. Clinical Trials Registration:NCT03011957.

Project description:BackgroundThe present study aimed to investigate longitudinal associations between bone mineral densities (BMDs) and appendicular skeletal muscle (ASM) mass in different regions of the body using three different indicators, in Chinese community-dwelling middle-aged and elderly men.MethodsA total of 1,343 men aged ≥ 40 years from a Chinese community were assessed at baseline (2014-2016), one-year follow-up (2016-2017; n = 648), two-year follow-up (2017-2018; n = 407), and three-year follow up (2018-2019; n = 208). At all the four time-points, measurements included ASM mass and BMDs for all regions of the body using dual-energy X-ray absorptiometry. A questionnaire was completed by patients and biochemical markers were assessed. We applied three different indicators to define ASM mass or lean mass respectively, including the appendicular skeletal muscle index (ASM adjusted by height, ASMI, according to the Asian Working Group for Sarcopenia), skeletal muscle index (ASM adjusted by weight, SMI, according to the International Working Group on Sarcopenia), and the appendicular skeletal muscle/body mass index (ratio of ASM and Body mass index (BMI), ASM/BMI, according to the Foundation for the National Institutes of Health). After adjusting for potential confounders, the generalized additive mixed model (GAMM) was used to analyze the trend in ASM mass over time, and to test the association between ASM mass and regional and whole-body BMDs.ResultsThe incidence of low lean mass was 8.2% defined by ASMI, 16.3% defined by SMI, and 8.3% defined by ASM/BMI. There was a linear relationship between BMDs and ASM mass, and ASMI, ASM/BMI, and SMI gradually decreased with time. After adjusting for covariances, GAMM analysis determined longitudinal associations between BMDs and ASM mass by three indicators respectively: the skull BMD was negatively associated with ASM mass. For each unit increase in skull BMD, ASMI decreased by 0.28 kg/m2 (95% confidence interval (CI) [-0.39 to -0.16]), ASM/BMI decreased by 0.02 m2 (95% CI [-0.03 to -0.00]), and SMI decreased by 0.01% (95% CI[-0.01 to -0.00]). The remaining parameters (including whole-body mean BMD, thoracic spinal BMD, lumbar spinal BMD, hip BMD, femoral neck BMD, pelvic BMD, left arm BMD, right arm BMD, left leg BMD, right leg BMD) were positively correlated with ASM mass. The ASMI increased by 3.07 kg/m2for each unit increase in the femoral neck BMD (95% CI [2.31-3.84]). The ASM/BMI increased by 0.22 m2for each unit increase in the left arm BMD (95% CI [0.12-0.33]), and the SMI increased by 0.05% per unit increase in the left arm BMD (95% CI [0.02-0.08]).ConclusionsCompared to ASMI and ASM/BMI, SMI was more sensitive to screen for the low lean mass. Skull BMD was negatively associated with ASM mass, while BMDs throughout the rest of the body were positively correlated with ASM mass among the middle-aged and elderly Chinese men.

Project description:BACKGROUND: Age-related physiological, biochemical and functional changes in mammalian skeletal muscle have been shown to begin at the mid-point of the lifespan. However, the underlying changes in DNA methylation that occur during this turning point of the muscle aging process have not been clarified. To explore age-related genomic methylation changes in skeletal muscle, we employed young (0.5 years old) and middle-aged (7 years old) pigs as models to survey genome-wide DNA methylation in the longissimus dorsi muscle using a methylated DNA immunoprecipitation sequencing approach. RESULTS: We observed a tendency toward a global loss of DNA methylation in the gene-body region of the skeletal muscle of the middle-aged pigs compared with the young group. We determined the genome-wide gene expression pattern in the longissimus dorsi muscle using microarray analysis and performed a correlation analysis using DMR (differentially methylated region)-mRNA pairs, and we found a significant negative correlation between the changes in methylation levels within gene bodies and gene expression. Furthermore, we identified numerous genes that show age-related methylation changes that are potentially involved in the aging process. The methylation status of these genes was confirmed using bisulfite sequencing PCR. The genes that exhibited a hypomethylated gene body in middle-aged pigs were over-represented in various proteolysis and protein catabolic processes, suggesting an important role for these genes in age-related muscle atrophy. In addition, genes associated with tumorigenesis exhibited aged-related differences in methylation and expression levels, suggesting an increased risk of disease associated with increased age. CONCLUSIONS: This study provides a comprehensive analysis of genome-wide DNA methylation patterns in aging pig skeletal muscle. Our findings will serve as a valuable resource in aging studies, promoting the pig as a model organism for human aging research and accelerating the development of comparative animal models in aging research.

Project description:Age-related methylation changes have been identified in various tissues and organisms, yet the underlying DNA methylation alterations in muscle aging process have not been clearly clarified. Whilst, many studies revealed that the structural and functional changes in skeletal muscle during aging process started from the mid-point of lifespan. In this study, we used pigs aged 0.5 year and 7 years, representing young and middle-aged periods. Using methylated DNA immunoprecipitation sequencing, we performed comprehensive genome-wide DNA methylation profiling for longissimus dorsi muscle in young and middle-aged pigs. We found more genes showed differently methylated in genebody. In details, 185 human ortholog genes contained DMRs that located in the promoter region, while 657 genes and 1063 genes with DMRs in gene body showed hypermethylation and hypomethylation in MA pigs, respectively. From the gene enrichment analysis, genebody hypermethylated genes showed significant enrichment for several molecular functions such as M-bM-^@M-^XGTPase regulator activityM-bM-^@M-^Y, M-bM-^@M-^XATP bindingM-bM-^@M-^Y and M-bM-^@M-^Xprotein kinase activityM-bM-^@M-^Y. Notably, genebody hypomethylated genes showed significant enrichment for various proteolysis and protein catabolic process. However, genes with DMR in their promoter region were not significantly enriched in any biology process. Proteolysis-associated genes, such as FOXO3 and FGFR1, showed different genebody methylation and mRNA expression level in two age groups, which may contribute to muscle atrophy during aging. Especially, other tumorigenesis-associated genes including GPI and GRB2, exhibited increasing mRNA level in middle-aged pigs, suggesting the possible higher risk of having cancer in human middle-aged period. Our results will serve as a valuable resource in aging studies, promote pig as a model organism for human aging research and accelerate the considerable development of comparative animal models in aging research. We collected the longissimus dorsi muscles tissue from Jinhua pigs which aged 0.5 year and seven years and study the genome-wide DNA methylation difference and the genome-wide gene expression profile between the two age periods. This submission represents transcriptome component of study.

Project description:BackgroundWomen experience drastic hormonal changes during midlife due to the menopausal transition. Menopausal hormonal changes are known to lead to bone loss and potentially also to loss of lean mass. The loss of muscle and bone tissue coincide due to the functional relationship and interaction between these tissues. If and how physical activity counteracts deterioration in muscle and bone during the menopausal transition remains partly unresolved. This study investigated differences between premenopausal, early perimenopausal, late perimenopausal, and postmenopausal women in appendicular lean mass (ALM), appendicular lean mass index (ALMI), femoral neck bone mineral density (BMD) and T score. Furthermore, we investigated the simultaneous associations of ALM and BMD with physical activity in the above-mentioned menopausal groups.MethodsData from the Estrogen Regulation of Muscle Apoptosis study were utilized. In total, 1393 women aged 47-55 years were assigned to premenopausal, early perimenopausal, late perimenopausal, and postmenopausal groups based on follicle-stimulating hormone concentration and bleeding diaries. Of them, 897 were scanned for ALM and femoral neck BMD by dual-energy X-ray absorptiometry and ALMI (ALM/height2 ) and neck T scores calculated. Current level of leisure-time physical activity was estimated by a validated self-report questionnaire and categorized as sedentary, low, medium, and high.ResultsAppendicular lean mass, appendicular lean mass index, femoral neck bone mineral density, and and T score showed a significant linear declining trend across all four menopausal groups. Compared with the postmenopausal women, the premenopausal women showed greater ALM (18.2, SD 2.2 vs. 17.8, SD 2.1, P < 0.001), ALMI (6.73, SD 0.64 vs. 6.52, SD 0.62, P < 0.001), neck BMD (0.969, SD 0.117 vs. 0.925, SD 0.108, P < 0.001), and T score (-0.093, SD 0.977 vs -0.459, SD 0.902, P < 0.001). After adjusting for potential confounding pathways, a higher level of physical activity was associated with greater ALM among the premenopausal [β = 0.171; confidence interval (CI) 95% 0.063-0.280], late perimenopausal (β = 0.289; CI 95% 0.174-0.403), and postmenopausal (β=0.278; CI 95% 0.179-0.376) women. The positive association between femoral neck BMD and level of physical activity was significant only among the late perimenopausal women (β = 0.227; CI 95% 0.097-0.356).ConclusionsSkeletal muscle and bone losses were associated with the menopausal transition. A higher level of physical activity during the different menopausal phases was beneficial, especially for skeletal muscle. Menopause-related hormonal changes predispose women to sarcopenia and osteoporosis and further to mobility disability and fall-related fractures in later life. New strategies are needed to promote physical activity among middle-aged women. Longitudinal studies are needed to confirm these results.

Project description:Background: Age-related physiological, biochemical and functional changes in mammalian skeletal muscle have been shown to begin at the mid-point of the lifespan. However, the underlying changes in DNA methylation that occur during this turning point of the muscle aging process have not been clarified. To explore age-related genomic methylation changes in skeletal muscle, we employed young (0.5 years old) and middle-aged (7 years old) pigs as models to survey genome-wide DNA methylation in the longissimus dorsi muscle using a methylated DNA immunoprecipitation sequencing approach. Results: We observed a tendency toward a global loss of DNA methylation in the gene-body region of the skeletal muscle of the middle-aged pigs compared with the young group. We determined the genome-wide gene expression pattern in the longissimus dorsi muscle using microarray analysis and performed a correlation analysis using DMR (differentially methylated region)-mRNA pairs, and we found a significant negative correlation between the changes in methylation levels within gene bodies and gene expression. Furthermore, we identified numerous genes that show age-related methylation changes that are potentially involved in the aging process. The methylation status of these genes was confirmed using bisulfite sequencing PCR. The genes that exhibited a hypomethylated gene body in middle-aged pigs were over-represented in various proteolysis and protein catabolic processes, suggesting an important role for these genes in age-related muscle atrophy. In addition, genes associated with tumorigenesis exhibited aged-related differences in methylation and expression levels, suggesting an increased risk of disease associated with increased age. Conclusions: This study provides a comprehensive analysis of genome-wide DNA methylation patterns in aging pig skeletal muscle. Our findings will serve as a valuable resource in aging studies, promoting the pig as a model organism for human aging research and accelerating the development of comparative animal models in aging research. We collected the longissimus dorsi muscles tissue from Jinhua pigs which aged 0.5 year and seven years and study the genome-wide DNA methylation difference between the two age periods.

Dataset Information

Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice.

Publications

Short-term pharmacologic RAGE inhibition differentially affects bone and skeletal muscle in middle-aged mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets