scholarly journals Hallmarks of frailty and osteosarcopenia in prematurely aged PolgAD257A/D257A mice

2019 ◽  
Author(s):  
Ariane C. Scheuren ◽  
Gommaar D’Hulst ◽  
Gisela A. Kuhn ◽  
Evi Masschelein ◽  
Esther Wehrle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Musculoskeletal System ◽  
Volume Fraction ◽  
Frailty Index ◽  
Bone Adaptation ◽  
Geriatric Syndrome ◽  
Bone Volume Fraction ◽  
Age Related ◽  
Caudal Vertebrae

AbstractBackgroundFrailty is a geriatric syndrome characterized by increased susceptibility to adverse health outcomes. One major determinant thereof is the gradual weakening of the musculoskeletal system and the associated osteosarcopenia. To improve our understanding of the underlying pathophysiology and, more importantly, to test potential interventions aimed at counteracting frailty suitable animal models are needed.MethodsTo evaluate the relevance of prematurely aged PolgA(D257A/D257A) mice as a model for frailty and osteosarcopenia, we quantified the clinical mouse frailty index in PolgA(D257A/D257A) and wild type littermates (PolgA(+/+), WT) with age and concertedly assessed the quantity and quality of bone and muscle tissue. Lastly, the anabolic responsiveness of skeletal muscle, muscle progenitors and bone was assessed.ResultsPolgA(D257A/D257A) accumulated health deficits at a higher rate compared to WT, resulting in a higher frailty index at 40 and 46 weeks of age (+166%, +278%, p<0.0001), respectively, with no differences between genotypes at 34 weeks. Concomitantly, PolgA(D257A/D257A) displayed progressive musculoskeletal deterioration such as reduced bone and muscle mass as well as impaired functionality thereof. In addition to lower muscle weights (-14%, p<0.05, -23%, p<0.0001) and fiber area (-20%, p<0.05, -22%, p<0.0001) at 40 and 46 weeks, respectively, PolgA(D257A/D257A) showed impairments in grip-strength and concentric muscle forces (p<0.05). PolgA(D257A/D257A) mutation altered the acute response to various anabolic stimuli in skeletal muscle and muscle progenitors. While PolgA(D257A/D257A) muscles were hypersensitive to eccentric contractions as well as leucine administration, shown by larger downstream signaling response of the mechanistic target of rapamycin complex 1 (mTORC1), myogenic progenitors cultured in vitro showed severe anabolic resistance to leucine and robust impairments in cell proliferation. Longitudinal micro-CT analysis of the 6th caudal vertebrae showed that PolgA(D257A/D257A) had lower bone morphometric parameters (e.g. bone volume fraction, trabecular and cortical thickness, p<0.05) as well as reduced remodeling activities (e.g. bone formation and resorption rate, p<0.05) compared to WT. When subjected to 4 weeks of cyclic loading, young but not aged PolgA(D257A/D257A) caudal vertebrae showed load-induced bone adaptation suggesting reduced mechanosensitivity with age.ConclusionsPolgA(D257A/D257A) mutation leads to hallmarks of age-related frailty and osteosarcopenia and provides a powerful model to better understand the relationship between frailty and the aging musculoskeletal system.

Impact of Thresholding Techniques on Micro-CT Image Based Computational Models of Trabecular Bone

2000 ◽  
Author(s):  
Mark J. Eichler ◽  
Chi Hyun Kim ◽  
Ralph Müller ◽  
X. Edward Guo
Keyword(s):  
Mechanical Properties ◽  
Trabecular Bone ◽  
Computational Models ◽  
Volume Fraction ◽  
Bone Fractures ◽  
Bone Adaptation ◽  
Bone Architecture ◽  
Micro Ct ◽  
Bone Volume Fraction ◽  
Age Related

Abstract Age-related bone fractures are mostly influenced by trabecular bone sites. Trabecular bone constantly adapts its bone volume fraction (BV/TV) and orientation, and thus its mechanical properties, to mechanical usage. Therefore, understanding the trabecular bone adaptation process and its consequences will contribute to the better understanding of the etiology of age-related fractures. Micro-computed tomography (micro-CT) is a relatively new method to quantify the complex three-dimensional (3D) trabecular bone architecture [1,2]. Finite element computational studies can be performed on these 3D microstructural images by converting each image voxel into an element [3,4,5]. Image thresholding techniques to segment bone voxels from bone marrow voxels have a major impact on the results of these models. However, the influence of different types of thresholding techniques on the mechanical properties of bone has not been examined carefully.

scholarly journals Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 345 ◽  
Author(s):  
Maria Borja-Gonzalez ◽  
Jose C. Casas-Martinez ◽  
Brian McDonagh ◽  
Katarzyna Goljanek-Whysall
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Muscle Hypertrophy ◽  
Myogenic Potential ◽  
Age Related ◽  
Primary Myoblasts ◽  
Muscle Homeostasis ◽  
Old Mice

Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and IL6, as well as H2O2, increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or IL6 treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating IL6R, PTEN and FOXO3 signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and IL6, within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration.

scholarly journals Gender-Specific Changes in Bone Turnover and Skeletal Architecture in Igfbp-2-Null Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2051-2061 ◽  
Author(s):  
V. E. DeMambro ◽  
D. R. Clemmons ◽  
L. G. Horton ◽  
M. L. Bouxsein ◽  
T. L. Wood ◽  
...  
Keyword(s):  
Bone Turnover ◽  
Volume Fraction ◽  
Fold Increase ◽  
Tartrate Resistant Acid Phosphatase ◽  
Bone Volume Fraction ◽  
Independent Manner ◽  
Insulin Resistant ◽  
Tensin Homolog ◽  
Igf I

IGF-binding protein-2 (IGFBP-2) is a 36-kDa protein that binds to the IGFs with high affinity. To determine its role in bone turnover, we compared Igfbp2−/− mice with Igfbp2+/+ colony controls. Igfbp2−/− males had shorter femurs and were heavier than controls but were not insulin resistant. Serum IGF-I levels in Igfbp2−/− mice were 10% higher than Igfbp2+/+ controls at 8 wk of age; in males, this was accompanied by a 3-fold increase in hepatic Igfbp3 and Igfbp5 mRNA transcripts compared with Igfbp2+/+ controls. The skeletal phenotype of the Igfbp2−/− mice was gender and compartment specific; Igfbp2−/− females had increased cortical thickness with a greater periosteal circumference compared with controls, whereas male Igfbp2−/− males had reduced cortical bone area and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae than Igfbp2+/+ controls. Serum osteocalcin levels were reduced by nearly 40% in Igfbp2−/− males, and in vitro, both CFU-ALP+ preosteoblasts, and tartrate-resistant acid phosphatase-positive osteoclasts were significantly less abundant than in Igfbp2+/+ male mice. Histomorphometry confirmed fewer osteoblasts and osteoclasts per bone perimeter and reduced bone formation in the Igfbp2−/− males. Lysates from both osteoblasts and osteoclasts in the Igfbp2−/− males had phosphatase and tensin homolog (PTEN) levels that were significantly higher than Igfbp2+/+ controls and were suppressed by addition of exogenous IGFBP-2. In summary, there are gender- and compartment-specific changes in Igfbp2−/− mice. IGFBP-2 may regulate bone turnover in both an IGF-I-dependent and -independent manner.

scholarly journals Age-Dependent Oxidative Stress Elevates Arginase 1 and Uncoupled Nitric Oxide Synthesis in Skeletal Muscle of Aged Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Chirayu D. Pandya ◽  
Byung Lee ◽  
Haroldo A. Toque ◽  
Bharati Mendhe ◽  
Robert T. Bragg ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Cell Survival ◽  
Bone Fractures ◽  
Arginase Activity ◽  
Aged Mice ◽  
Arginase 1 ◽  
Age Related ◽  
Stress Dependent

Aging is associated with reduced muscle mass (sarcopenia) and poor bone quality (osteoporosis), which together increase the incidence of falls and bone fractures. It is widely appreciated that aging triggers systemic oxidative stress, which can impair myoblast cell survival and differentiation. We previously reported that arginase plays an important role in oxidative stress-dependent bone loss. We hypothesized that arginase activity is dysregulated with aging in muscles and may be involved in muscle pathophysiology. To investigate this, we analyzed arginase activity and its expression in skeletal muscles of young and aged mice. We found that arginase activity and arginase 1 expression were significantly elevated in aged muscles. We also demonstrated that SOD2, GPx1, and NOX2 increased with age in skeletal muscle. Most importantly, we also demonstrated elevated levels of peroxynitrite formation and uncoupling of eNOS in aged muscles. Our in vitro studies using C2C12 myoblasts showed that the oxidative stress treatment increased arginase activity, decreased cell survival, and increased apoptotic markers. These effects were reversed by treatment with an arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH). Our study provides strong evidence that L-arginine metabolism is altered in aged muscle and that arginase inhibition could be used as a novel therapeutic target for age-related muscle complications.

scholarly journals Voxel size dependency, reproducibility and sensitivity of an in vivo bone loading estimation algorithm

2016 ◽  
Vol 13 (114) ◽  
pp. 20150991 ◽  
Author(s):  
Patrik Christen ◽  
Friederike A. Schulte ◽  
Alexander Zwahlen ◽  
Bert van Rietbergen ◽  
Stephanie Boutroy ◽  
...  
Keyword(s):  
Volume Fraction ◽  
Estimation Algorithm ◽  
Bone Volume ◽  
Micro Ct ◽  
Bone Volume Fraction ◽  
Voxel Size ◽  
Size Dependency ◽  
Bone Loading

A bone loading estimation algorithm was previously developed that provides in vivo loading conditions required for in vivo bone remodelling simulations. The algorithm derives a bone's loading history from its microstructure as assessed by high-resolution (HR) computed tomography (CT). This reverse engineering approach showed accurate and realistic results based on micro-CT and HR-peripheral quantitative CT images. However, its voxel size dependency, reproducibility and sensitivity still need to be investigated, which is the purpose of this study. Voxel size dependency was tested on cadaveric distal radii with micro-CT images scanned at 25 µm and downscaled to 50, 61, 75, 82, 100, 125 and 150 µm. Reproducibility was calculated with repeated in vitro as well as in vivo HR-pQCT measurements at 82 µm. Sensitivity was defined using HR-pQCT images from women with fracture versus non-fracture, and low versus high bone volume fraction, expecting similar and different loading histories, respectively. Our results indicate that the algorithm is voxel size independent within an average (maximum) error of 8.2% (32.9%) at 61 µm, but that the dependency increases considerably at voxel sizes bigger than 82 µm. In vitro and in vivo reproducibility are up to 4.5% and 10.2%, respectively, which is comparable to other in vitro studies and slightly higher than in other in vivo studies. Subjects with different bone volume fraction were clearly distinguished but not subjects with and without fracture. This is in agreement with bone adapting to customary loading but not to fall loads. We conclude that the in vivo bone loading estimation algorithm provides reproducible, sensitive and fairly voxel size independent results at up to 82 µm, but that smaller voxel sizes would be advantageous.

Comparison of Mixed and Kinematic Uniform Boundary Conditions in Homogenized Elasticity of Femoral Trabecular Bone Using Microfinite Element Analyses

2015 ◽  
Vol 137 (1) ◽  
Author(s):  
Jarunan Panyasantisuk ◽  
Dieter H. Pahr ◽  
Thomas Gross ◽  
Philippe K. Zysset
Keyword(s):  
Boundary Conditions ◽  
Trabecular Bone ◽  
Elastic Properties ◽  
Elastic Constants ◽  
Volume Fraction ◽  
Bone Fragility ◽  
Model Parameters ◽  
Bone Volume Fraction ◽  
Age Related ◽  
Future Work

Mechanical properties of human trabecular bone play an important role in age-related bone fragility and implant stability. Microfinite element (μFE) analysis allows computing the apparent elastic properties of trabecular bone for use in homogenized FE (hFE) analysis, but the results depend unfortunately on the type of applied boundary conditions (BCs). In this study, 167 human femoral trabecular cubic regions with a side length of 5.3 mm were extracted from three proximal femora and analyzed using μFE analysis to compare systematically their stiffness with kinematic uniform BCs (KUBCs) and periodicity-compatible mixed uniform BCs (PMUBCs). The obtained elastic constants were then used in the volume fraction and fabric-based orthotropic Zysset–Curnier model to identify their respective model parameters. As expected, PMUBCs lead to more compliant apparent elastic properties than KUBCs, especially in shear. The differences in stiffness decreased with bone volume fraction and mean intercept length (MIL). Unlike KUBCs, PMUBCs were sensitive to heterogeneity of the biopsies. The Zysset–Curnier model fitted the apparent elastic constants successfully in both cases with adjusted coefficients of determination (radj2) of 0.986 for KUBCs and 0.975 for PMUBCs. The proper use of these BCs for hFE analysis of whole bones will need to be investigated in future work.

scholarly journals Early-Onset Type 2 Diabetes Impairs Skeletal Acquisition in the Male TALLYHO/JngJ Mouse

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3806-3816 ◽  
Author(s):  
M. J. Devlin ◽  
M. Van Vliet ◽  
K. Motyl ◽  
L. Karim ◽  
D. J. Brooks ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Marrow ◽  
Bone Mass ◽  
Early Onset ◽  
Volume Fraction ◽  
Mineral Density ◽  
Bone Volume Fraction ◽  
Skeletal Acquisition

Abstract Type 2 diabetes (T2D) incidence in adolescents is rising and may interfere with peak bone mass acquisition. We tested the effects of early-onset T2D on bone mass, microarchitecture, and strength in the TALLYHO/JngJ mouse, which develops T2D by 8 weeks of age. We assessed metabolism and skeletal acquisition in male TALLYHO/JngJ and SWR/J controls (n = 8–10/group) from 4 weeks to 8 and 17 weeks of age. Tallyho mice were obese; had an approximately 2-fold higher leptin and percentage body fat; and had lower bone mineral density vs SWR at all time points (P &lt; .03 for all). Tallyho had severe deficits in distal femur trabecular bone volume fraction (−54%), trabecular number (−27%), and connectivity density (−82%) (P &lt; .01 for all). Bone formation was higher in Tallyho mice at 8 weeks but lower by 17 weeks of age vs SWR despite similar numbers of osteoblasts. Bone marrow adiposity was 7- to 50-fold higher in Tallyho vs SWR. In vitro, primary bone marrow stromal cell differentiation into osteoblast and adipocyte lineages was similar in SWR and Tallyho, suggesting skeletal deficits were not due to intrinsic defects in Tallyho bone-forming cells. These data suggest the Tallyho mouse might be a useful model to study the skeletal effects of adolescent T2D.

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