Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia

Speacht, Toni L.; Krause, Andrew R.; Steiner, Jennifer L.; Lang, Charles H.; Donahue, Henry J.

doi:10.1016/j.bone.2018.01.026

Cited by 22 publications

(52 citation statements)

References 62 publications

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“…The Control − TC group represented age‐related bone loss as this limb would have normal weight distribution throughout the study, albeit potentially having small systemic effects from periodic anesthesia and loading the contralateral limb. The HLS − TC group, consistent with previous studies, showed significant bone loss from suspension …”

Section: Discussionsupporting

confidence: 91%

“…It was also found that there were significant decreases in the absolute mass of gastrocnemius and quadriceps muscles, increases in atrogenes, MuRF1 and Atrogin‐1, and a significant decrease in muscle protein synthesis on days 7 to 14 . There are numerous other reports in the literature reporting significant bone and muscle loss with the hindlimb‐suspension model with as little as 14‐day suspension …”

Section: Introductionmentioning

confidence: 84%

“…A modified model of hindlimb suspension was utilized, originally described by Morey‐Holton and Globus, and previously reported . Mice were suspended under anesthesia with isoflurane (2% delivered in 100% oxygen) at the conclusion of day 0 μCT scans.…”

Section: Methodsmentioning

confidence: 99%

“…Images were Gaussian‐filtered (sigma = 1.5, support = 2), and a 27.5% threshold was used to remove soft tissue. Trabecular sections from the proximal tibia, immediately distal to the growth plate, were evaluated over a 72‐slice region consistent with previous reports . Cortical sections from the midshaft and distal shaft of the tibia were evaluated, each over a 22‐slice region.…”

Section: Methodsmentioning

confidence: 99%

“…In vivo mechanical loading, creating higher strain environments, can induce an osteogenic atmosphere. in vivo loading models of turkey radius/ulna, rat femur/tibia, and murine femur/tibia have been reported . The tibial‐compression loading model is a popular noninvasive method shown to induce an anabolic response in both trabecular and cortical bone compartments.…”

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Controlled Mechanical Loading of Bone in C57BL6/J Mice Subject to Disuse

et al. 2019

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Prolonged reduction in weightbearing causes bone loss. Disuse of bone is associated with recovery from common musculoskeletal injury and trauma, bed rest resulting from various medical conditions, and spaceflight. The hindlimb‐suspension rodent model is popular for simulating unloading and disuse. We hypothesized that controlled mechanical loading of the tibia would protect against bone loss occurring from concurrent disuse. Additionally, we hypothesized that areas of high mechanical peak strains (midshaft) would provide more protection than areas of lower strain (distal shaft). Adult C57BL6/J mice were suspended for 3 weeks, with one limb subjected to tibial compression four times per week. μCT imaging was completed at days 0, 11, and 21, in addition to serum analysis. Significant bone loss caused by hindlimb suspension was detected in trabecular bone by day 11 and worsened by day 21 (p < 0.05). Bone loss was also detected in cortical thickness and area fraction by day 21. However, four short bouts per week of compressive loading protected the loaded limb from much of this bone loss. At day 21, we observed a 50% loss in trabecular bone volume/total volume and a 6% loss in midshaft cortical thickness in unloaded limbs, but only 15% and 2% corresponding losses in contralateral loaded limbs (p = 0.001 and p = 0.02). Many bone geometry parameters of the loaded limbs of suspended animals did not significantly differ from non‐suspended control limbs. Conversely, this protective effect of loading was not detected in cortical bone at the lower‐strained distal shaft. Analysis of bone metabolism markers suggested that the benefits of loading occurred through increased formation instead of decreased resorption. This study uniquely isolates the role of externally applied mechanical loading of the mouse tibia, in the absence of muscle stimulation, in protecting bone from concurrent disuse‐related loss, and demonstrates that limited bouts of loading may be highly effective during prolonged disuse. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Protective Effects of Controlled Mechanical Loading of Bone in C57BL6/J Mice Subject to Disuse

et al. 2019

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Bone structural, biomechanical, and histomorphometric characteristics of the hindlimb skeleton in the marsh rice rat (Oryzomys palustris)

Castillo

Croft

Jiron

et al. 2022

The Anatomical Record

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The rice rat (Oryzomys palustris) is a nonconventional laboratory rodent species used to model some human bone disorders. However, no studies have been conducted to characterize the postcranial skeleton. Therefore, we aimed to investigate age‐ and gender‐related features of the hindlimb skeleton of this species. We used femurs and tibiae from 94 rats of both genders aged 4–28 weeks. Bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties were determined in femurs. In addition, bone histomorphometry of tibiae was conducted to assess bone cell activities and bone turnover over time. Bone length, total metaphysis BMC and vBMD, mid‐diaphyseal BMC and vBMD, cortical thickness, and cortical area progressively augmented with age. Whereas the increase in these parameters plateaued at age 16–22 weeks in female rats, they continued to rise to age 28 weeks in male rats. Furthermore, bone strength parameters increased with age, with few differences between genders. We also observed a rapid decrease in longitudinal growth between age 4 and 16 weeks. Whereas young rats had a greater bone formation rate and bone turnover, older rice rats had greater bone volume and trabecular thickness, with no differences between genders. (a) Sexual dimorphism in the rice rat becomes grossly evident at age 16 weeks; (b) the age‐related increases in bone mass, structural cortical parameters, and in some biomechanical property parameters plateau at an older age in male than in female rats; and (c) bone growth and remodeling significantly decreased with age irrespective of the gender.

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Denervation‐induced loss of skeletal muscle mass influences immune homeostasis and accelerates the disease progression of lupus nephritis

Liu

Kiyoi

Takemasa

et al. 2020

JCSM Clinical Reports

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BackgroundPatients with systemic autoimmune disease are predisposed to developing sarcopenia associated with their underlying proinflammatory condition and a decrease in motility. How sarcopenic status affects disease progression remains unknown. The present study explored the influence of denervation‐induced sarcopenia on immune homeostasis and investigated related biological pathways that might be important for future disease management.MethodsA denervation‐induced skeletal muscle loss model was established, and the function of the immune system was evaluated. Immune cell proportions and cytokine levels in peripheral blood and atrophied skeletal muscle were profiled. We examined store‐operated Ca2+ entry and mitochondrial function in immune cells. MRL/lpr mice were used to evaluate the influence of denervation‐induced sarcopenia on autoimmune progression in lupus nephritis.ResultsCompared with splenocyte fractions obtained from sham mice, proportions of CD4+ cells, CD8+ cells, CD19+CD20− cells, CD49b+NK46+ cells, CD4+IL‐4+ cells, and CD4+FoxP3+ cells were significantly decreased, whereas CD19+CD20+ cells, CD4+IFN‐γ+ cells, and CD4+IL17+ cells were markedly increased in sciatic nerve axotomy (SNA) mice. The serum cytokine profile indicated that SNA significantly increased the protein expressions of IL‐12p70 (P = 0.014), IL‐17A (P = 0.007), and IFN‐γ (P < 0.001). In SNA mice, there was an 18.74% decrease in peak Ca2+ influx (P < 0.001) and an 18.22% decrease in initial Ca2+ influx (P < 0.001) rates in peripheral T cells compared with sham mice. Mitochondrial respiration was significantly reduced in peripheral T cells from SNA mice compared with sham mice. SNA substantially promoted disease progression in lupus model mice demonstrated by the results of proteinuria monitoring, serum levels of blood urea nitrogen, and kidney histological scores.ConclusionsThe loss of skeletal muscle impaired mitochondrial respiration and activation in T cells and influenced the balance of T helper cell subsets. Therefore, denervation‐induced sarcopenia might promote the progression of autoimmune diseases, such as lupus nephritis, and enhance Th1/Th17 functions. These results suggest that physicians should be aware of the impact of the loss of skeletal muscle on the management of autoimmune disease and that a multidisciplinary approach is required to minimize the overall adverse impact of sarcopenia.

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Combination of hindlimb suspension and immobilization by casting exaggerates sarcopenia by stimulating autophagy but does not worsen osteopenia

Cited by 22 publications

References 62 publications

Protective Effects of Controlled Mechanical Loading of Bone in C57BL6/J Mice Subject to Disuse

Protective Effects of Controlled Mechanical Loading of Bone in C57BL6/J Mice Subject to Disuse

Bone structural, biomechanical, and histomorphometric characteristics of the hindlimb skeleton in the marsh rice rat (Oryzomys palustris)

Denervation‐induced loss of skeletal muscle mass influences immune homeostasis and accelerates the disease progression of lupus nephritis

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