Chronic kidney disease and aging differentially diminish bone material and microarchitecture in C57Bl/6 mice

Heveran, Chelsea M.; Schurman, Charles A.; Acevedo, Claire; Livingston, Eric W.; Howe, Danielle; Schaible, Eric; Hunt, Heather B.; Rauff, Adam; Donnelly, Eve; Carpenter, R. Dana; Levi, Moshe; Lau, Anthony G.; Bateman, Ted A.; Alliston, Tamara; King, Karen B.; Ferguson, Virginia L.

doi:10.1016/j.bone.2019.04.019

Cited by 41 publications

(42 citation statements)

References 55 publications

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“…15 Here we measured total fluorescent AGE accumulation using previously established fluorescence measurements at 360 nm excitation and 460 nm emission. 24,29,43,52,[56][57][58][59][60][61] These specific wavelengths are consistent with all AGEs that naturally fluoresce, including pentosidine, pentodilysine, crossline, pyrropyridine, Vespertysine A, Vespertysine C, and fluorescent AGE adducts. 15 In addition to measuring fluorescent AGE accumulation we also measured AGE crosslink pentosidine auto-fluorescence.…”

Section: Discussionsupporting

confidence: 61%

“…Fluorometric assays were carried out to assess the effects of ribose and riboflavin-465 nm on the formation of fluorescent AGEs and the AGE crosslink, pentosidine, as previously described. 7,24,29,43,52,[56][57][58][59][60][61] Briefly, crosslinks were quantified by fluorescence using a Biotek Synergy HTX Multi-Mode Reader at two different ranges of wavelengths. General fluorescent AGEs were quantified by reading fluorescence at 360 nm excitation, 460 nm emission and compared to quinine standards (Sigma-Aldrich) as previously reported.…”

Section: Fluorescent Age Quantificationmentioning

confidence: 99%

“…General fluorescent AGEs were quantified by reading fluorescence at 360 nm excitation, 460 nm emission and compared to quinine standards (Sigma-Aldrich) as previously reported. 24,56,60,61 Pentosidine fluorescence was quantified by reading fluorescence at 328 nm excitation, 378 nm emission 7,52 and compared to pentosidine standards (Caymen Chemical). Fluorescence at 328 nm/378 nm excitation/emission is consistent with the formation of pentosidine crosslinks; 7,25-27,52,62 however this range is not specific to pentosidine and may include other auto-fluorescence.…”

Section: Fluorescent Age Quantificationmentioning

confidence: 99%

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An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

Gouldin

Puetzer

2020

Preprint

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In connective tissues there is a clear link between increasing age and degeneration. It is believed advanced glycation end-products (AGEs) play a central role in this degeneration. AGEs are sugar induced non-enzymatic crosslinks which accumulate in collagen with age and diabetes, altering tissue mechanics and cellular function. Despite ample correlative evidence linking collagen glycation to degeneration, little is known how AGEs impact cell-matrix interactions, limiting therapeutic options. One reason for this limited understanding is AGEs are typically induced in vitro using high concentrations of ribose which decrease cell viability and make it impossible to investigate cell-matrix interactions. The objective of this study was to develop a system to trigger AGE accumulation while maintaining cell viability. Using cell-seeded high density collagen gels, we investigated the effect of two different systems for AGE induction, ribose at low concentrations (30, 100, and 200 mM) over 15 days of culture and riboflavin (0.25 mM and 0.75mM) induced with blue light for 40 seconds. We found ribose and riboflavin with blue light are capable of producing a wide range of AGE crosslinks which match and/or exceed reported human AGE levels for various tissues, ages, and diseases, without affecting cell viability and metabolism. Interestingly, a single 40 second treatment of riboflavin and blue light produced similar levels of AGEs as 3 days of 100 mM ribose treatment and matched aged mouse tendon AGE levels. This riboflavin treatment option is an exciting means to trigger AGE crosslinks on demand in vivo or in vitro without impacting cell metabolism or viability and holds great promise for further unraveling the mechanism of AGEs in age and diabetes related tissue degeneration.

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Section: Discussionsupporting

confidence: 61%

Section: Fluorescent Age Quantificationmentioning

confidence: 99%

Section: Fluorescent Age Quantificationmentioning

confidence: 99%

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An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

Gouldin

Puetzer

2020

Preprint

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“…At the experimental level, models of premature aging, such as Klotho-hypomorphic mice, develop earlystage CKD. In addition, other authors have recently described that uremic environment increases with aging in the experimental CKD model (Heveran et al, 2019). However, no studies have described overlapping effects of CKD and aging on cardiac function.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca²⁺ handling

Navarro‐García

Rueda

Romero‐García

et al. 2020

British J Pharmacology

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Background and Purpose Klotho is a membrane‐bound or soluble protein, originally identified as an age‐suppressing factor and regulator of mineral metabolism. Klotho deficiency is associated with the development of renal disease, but its role in cardiac function in the context of uraemic cardiomyopathy is unknown. Experimental Approach We explored the effects of Klotho on cardiac Ca2+ cycling. We analysed Ca2+ handling in adult cardiomyocytes from Klotho‐deficient (kl/kl) mice and from a murine model of 5/6 nephrectomy (Nfx). We also studied the effect of exogenous Klotho supplementation, by chronic recombinant Klotho treatment, or endogenous Klotho overexpression, using transgenic mice overexpressing Klotho (Tg‐Kl), on uraemic cardiomyopathy. Hearts from Nfx mice were used to study Ca2+ sensitivity of ryanodine receptors and their phosphorylation state. Key Results Cardiomyocytes from kl/kl mice showed decreased amplitude of intracellular Ca2+ transients and cellular shortening together with an increase in pro‐arrhythmic Ca2+ events compared with cells from wild‐type mice. Cardiomyocytes from Nfx mice exhibited the same impairment in Ca2+ cycling as kl/kl mice. Changes in Nfx cardiomyocytes were explained by higher sensitivity of ryanodine receptors to Ca2+ and their increased phosphorylation at the calmodulin kinase type II and protein kinase A sites. Ca2+ mishandling in Nfx‐treated mice was fully prevented by chronic recombinant Klotho administration or transgenic Klotho overexpression. Conclusions and Implications Klotho emerges as an attractive therapeutic tool to improve cardiac Ca2+ mishandling observed in uraemic cardiomyopathy. Strategies that improve Klotho availability are good candidates to protect the heart from functional cardiac alterations in renal disease.

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“…(48,49) However, with aging, cortical bone is thinner, with similar cross-sectional area, higher moment of area, and increased porosity. (49)(50)(51) These structural variations, together with inferior bone material properties, such as the reduced flexural modulus and collagen strain, (49,51,52) change the mechanical properties of the aging mouse bone at 20 months, increasing the strains on the bone surface. Sexually dimorphic bone structure and material properties may also explain the differences we observed in the strain magnitude and distribution on the tibia surface, with female mouse bone always having higher strains than tibias in male mice.…”

Section: Discussionmentioning

confidence: 99%

Age and Sex Differences in Load‐Induced Tibial Cortical Bone Surface Strain Maps

et al. 2021

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Bone adapts its architecture to the applied load; however, it is still unclear how bone mechano-adaptation is coordinated and why potential for adaptation adjusts during the life course. Previous animal models have suggested strain as the mechanical stimulus for bone adaptation, but yet it is unknown how mouse cortical bone load-related strains vary with age and sex. In this study, full-field strain maps (at 1 N increments up to 12 N) on the bone surface were measured in young, adult, and old (aged 10, 22 weeks, and 20 months, respectively), male and female C57BL/6J mice with load applied using a noninvasive murine tibial model. Strain maps indicate a nonuniform strain field across the tibial surface, with axial compressive loads resulting in tension on the medial side of the tibia because of its curved shape. The load-induced surface strain patterns and magnitudes show sexually dimorphic changes with aging. A comparison of the average and peak tensile strains indicates that the magnitude of strain at a given load generally increases during maturation, with tibias in female mice having higher strains than in males. The data further reveal that postmaturation aging is linked to sexually dimorphic changes in average and maximum strains. The strain maps reported here allow for loading male and female C57BL/6J mouse legs in vivo at the observed ages to create similar increases in bone surface average or peak strain to more accurately explore bone mechano-adaptation differences with age and sex.

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Chronic kidney disease and aging differentially diminish bone material and microarchitecture in C57Bl/6 mice

Cited by 41 publications

References 55 publications

An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca²⁺ handling

Age and Sex Differences in Load‐Induced Tibial Cortical Bone Surface Strain Maps

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Chronic kidney disease and aging differentially diminish bone material and microarchitecture in C57Bl/6 mice

Cited by 41 publications

References 55 publications

An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca2+ handling

Age and Sex Differences in Load‐Induced Tibial Cortical Bone Surface Strain Maps

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Enhanced Klotho availability protects against cardiac dysfunction induced by uraemic cardiomyopathy by regulating Ca²⁺ handling