The relative importance of genetics and phenotypic plasticity in dictating bone morphology and mechanics in aged mice: Evidence from an artificial selection experiment

Middleton, Kevin M.; Shubin, Corinne E.; Moore, Douglas C.; Carter, Patrick A.; Garland, Theodore; Swartz, Sharon M.

doi:10.1016/j.zool.2007.06.003

Cited by 24 publications

(54 citation statements)

References 112 publications

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“…Exactly how to control for type I error due to multiple comparisons is controversial in the literature, especially when several of the comparisons are presented only for completeness and several factors and covariates are primarily nuisance variables (e.g. Middleton et al, 2008). Therefore, for simplicity, we present two-tailed P values throughout.…”

Section: Statistical Analysesmentioning

confidence: 99%

Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running

Gomes

Rezende

Malisch

et al. 2009

Journal of Experimental Biology

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SUMMARYTo examine the evolution of endurance-exercise behaviour, we have selectively bred four replicate lines of laboratory mice (Mus domesticus) for high voluntary wheel running (ʻhigh runnerʼ or HR lines), while also maintaining four non-selected control (C) lines. By generation 16, HR mice ran ~2.7-fold more than C mice, mainly by running faster (especially in females), a differential maintained through subsequent generations, suggesting an evolutionary limit of unknown origin. We hypothesized that HR mice would have higher glycogen levels before nightly running, show greater depletion of those depots during their more intense wheel running, and have increased glycogen synthase activity and GLUT-4 protein in skeletal muscle. We sampled females from generation 35 at three times (photophase 07:00 h-19:00 h) during days 5-6 of wheel access, as in the routine selection protocol: Group 1, day 5, 16:00 h-17:30 h, wheels blocked from 13:00 h; Group 2, day 6, 02:00 h-03:30 h (immediately after peak running); and Group 3, day 6, 07:00 h-08:30 h. An additional Group 4, sampled 16:00 h-17:30 h, never had wheels. HR individuals with the mini-muscle phenotype (50% reduced hindlimb muscle mass) were distinguished for statistical analyses comparing C, HR normal, and HR mini. HR mini ran more than HR normal, and at higher speeds, which might explain why they have been favored by the selective-breeding protocol. Plasma glucose was higher in Group 1 than in Group 4, indicating a training effect (phenotypic plasticity). Without wheels, no differences in gastrocnemius GLUT-4 were observed. After 5 days with wheels, all mice showed elevated GLUT-4, but HR normal and mini were 2.5-fold higher than C. At all times and irrespective of wheel access, HR mini showed approximately three-fold higher [glycogen] in gastrocnemius and altered glycogen synthase activity. HR mini also showed elevated glycogen in soleus when sampled during peak running. All mice showed some glycogen depletion during nightly wheel running, in muscles and/or liver, but the magnitude of this depletion was not large and hence does not seem to be limiting to the evolution of even-higher wheel running. Supplementary material available online at

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Section: Statistical Analysesmentioning

confidence: 99%

Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running

Gomes

Rezende

Malisch

et al. 2009

Journal of Experimental Biology

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“…Although the mechanosensitivity of bone is undisputed, it is not the case that diaphyseal structure results solely from physiological adaptation to applied loads. Diaphyseal structure is also influenced by genetics (Eisman, 1999; Peacock et al, 2002; Middleton et al, 2008a), as well as nutrition, hormones, age, and other factors (for reviews in the anthropological literature, see Churchill, 1999; Chiu and Hamrick, 2002; Lovejoy et al, 2003; Pearson and Lieberman, 2004). …”

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confidence: 99%

Functional significance of genetic variation underlying limb bone diaphyseal structure

Wallace

Middleton

Lublinsky

et al. 2010

American J Phys Anthropol

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Limb bone diaphyseal structure is frequently used to infer hominin activity levels from skeletal remains, an approach based on the well-documented ability of bone to adjust to its loading environment during life. However, diaphyseal structure is also determined in part by genetic factors. This study investigates the possibility that genetic variation underlying diaphyseal structure is influenced by the activity levels of ancestral populations and might also have functional significance in an evolutionary context. We adopted an experimental evolution approach and tested for differences in femoral diaphyseal structure in one-week-old mice from a line that had been artificially selected (45 generations) for high voluntary wheel running and unselected controls. As adults, selected mice are significantly more active on wheels and in home cages, and have thicker diaphyses. Structural differences at one week can be assumed to primarily reflect the effects of selective breeding rather than direct mechanical stimuli, given that the onset of locomotion in mice is shortly after day seven. We hypothesized that if genetically determined diaphyseal structure reflects the activity patterns of members of a lineage, then selected animals will have relatively larger diaphyseal dimensions at one week compared to controls. The results provide strong support for this hypothesis and suggest that limb bone cross sections may not always only reflect the activity levels of particular fossil individuals, but also convey an evolutionary signal providing information about hominin activity in the past.Keywords cross-sectional geometry; genes; activity; artificial selection Anthropologists frequently use limb bone diaphyseal structure 1 to infer behavior, particularly activity levels, from skeletal remains. Individuals with thick diaphyses are (Larsen, 1997;Ruff, 2000). This paradigm is based on the well-documented ability of diaphyseal bone to adjust its structure during life to its mechanical environment (Goodship and Cunningham, 2001 and references therein). Generally, increased loading shifts the balance between bone's formative and resorptive activity towards net formation, while disuse causes net resorption. Although the mechanosensitivity of bone is undisputed, it is not the case that diaphyseal structure results solely from physiological adaptation to applied loads. Diaphyseal structure is also influenced by genetics (Eisman, 1999;Peacock et al., 2002;Middleton et al., 2008a), as well as nutrition, hormones, age, and other factors (for reviews in the anthropological literature, see Churchill, 1999;Chiu and Hamrick, 2002;Lovejoy et al., 2003;Pearson and Lieberman, 2004).The effect of genetics on modulating structure, independent of mechanical signals, is implied by analyses of juvenile human remains from geographically and temporally dispersed contexts which have shown that populational differences in gross diaphyseal dimensions emerge very early in ontogeny (e.g., Cowgill and Hager, 2007;Robbins, 2007;Cowgill, 2008). For exa...

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“…This site can be studied either in its entirety, 17,23 or in a subregion (for example 0.15 mm) centred at the narrowest point. 6,24 Cortical bone. If the procedures discussed in section 'Scan region' for midshaft scanning are followed for obtaining a consistent scan size for each animal and time point, the entire region can be analysed.…”

Section: B10mentioning

confidence: 99%

Quantitative analysis of bone and soft tissue by micro-computed tomography: applications to ex vivo and in vivo studies

Campbell¹,

Sophocleous²

2014

BoneKEy Reports

124

106

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Micro-computed tomography (micro-CT) is a high-resolution imaging modality that is capable of analysing bone structure with a voxel size on the order of 10 mm. With the development of in vivo micro-CT, where disease progression and treatment can be monitored in a living animal over a period of time, this modality has become a standard tool for preclinical assessment of bone architecture during disease progression and treatment. For meaningful comparison between micro-CT studies, it is essential that the same parameters for data acquisition and analysis methods be used. This protocol outlines the common procedures that are currently used for sample preparation, scanning, reconstruction and analysis in micro-CTstudies. Scan and analysis methods for trabecular and cortical bone are covered for the femur, tibia, vertebra and the full neonate body of small rodents. The analysis procedures using the software provided by ScancoMedical and Bruker are discussed, and the routinely used bone architectural parameters are outlined. This protocol also provides a section dedicated to in vivo scanning and analysis, which covers the topics of anaesthesia, radiation dose and image registration. Because of the expanding research using micro-CT to study other skeletal sites, as well as soft tissues, we also provide a review of current techniques to examine the skull and mandible, adipose tissue, vasculature, tumour severity and cartilage. Lists of recommended further reading and literature references are included to provide the reader with more detail on the methods described.

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The relative importance of genetics and phenotypic plasticity in dictating bone morphology and mechanics in aged mice: Evidence from an artificial selection experiment

Cited by 24 publications

References 112 publications

Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running

Glycogen storage and muscle glucose transporters (GLUT-4) of mice selectively bred for high voluntary wheel running

Functional significance of genetic variation underlying limb bone diaphyseal structure

Quantitative analysis of bone and soft tissue by micro-computed tomography: applications to ex vivo and in vivo studies

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