Lamia, S. | bioRxiv Science

bioRxiv2026

Bone Response to Mechanical Loading is Highly Heritable and Correlates with Osteocyte Lacunar Morphology in Genetically Diverse Mouse Strains

Skeletal loading is a key regulator of bone formation. Studies using in vivo loading of rodent bones have established many mechanical and biological factors that regulate bone response to loading. However, most studies have been performed in a small number of inbred rodent strains, and there are few data on effects of genetic background on the loading response. In the current study we employed two murine models of genetic diversity, the Diversity Outbred (DO) and their eight founder inbred strains, to assess the influence of genetic background on skeletal response to tibial loading. Loading-induced periosteal bone formation rates and formed bone volumes varied significantly among inbred mouse strains. DO mice, which each carry a unique mixture of alleles of the inbred founder strains, were more responsive to loading, on average, than the the inbred founder strains. Additionally, bone response to mechanical loading was highly heritable; broad-sense heritability for measures of periosteal formation were near or above 80%. Furthermore, osteocyte lacunar morphology correlated with loading response across inbred strains. Inbred 129S1 mice had the most elongated lacunae and exhibited the highest magnitude of response on both periosteal and endocortical surfaces. 129S1 also demonstrated a robust transcriptional response to loading, although the pathways induced by loading were largely conserved with lab-standard C57Bl/6. Together, these findings demonstrate that genetic background significantly contributes to bone response to loading and establish DO mice as a platform for discovery of genes that regulate skeletal mechanoresponsiveness.

bioengineering↗

bioRxiv2025

AMPK signaling is dysregulated in human tendinopathy and loss of AMPKα1 leads to cell, matrix and mechanical dysfunction in mouse Achilles tendon

Tendinopathy is a debilitating tendon disorder affecting millions of people, characterized by pain, swelling, and diminished biomechanical properties. While the precise mechanisms underlying tendon homeostasis remain unclear, metabolic regulation plays a critical role. In this study, we combine transcriptomic analysis of human tendinopathic samples with a conditional mouse model in which Prkaa1 (encoding AMPK1) is selectively deleted in tendon progenitors to elucidate the role of AMPK signaling in tendon homeostasis. RNA sequencing of diseased human tendons revealed downregulation of key metabolic genes, including several involved in the mitochondrial electron transport chain and AMPK signaling pathways, alongside an increase in markers associated with senescence and a secretory inflammatory profile. In parallel, mice with loss of Prkaa1 function exhibited normal postnatal development; however, by one month of age, tendons demonstrated widespread transcriptional alterations related to cell cycle regulation and ECM organization. By three months, AMPK1-deficient tendons showed significant reductions in mechanical strength and increased expression of senescence markers p21 and p16, progressing to prominent ectopic calcification with age. In vitro studies further confirmed that tendon fibroblasts lacking AMPK1 have altered ECM substrate adhesion profiles. Importantly, voluntary exercise partially rescued these deficits by enhancing ECM organization and reducing senescence marker expression. Collectively, our findings demonstrate that AMPK1 is critical for maintaining energy balance, regulating ECM remodeling, and preventing premature cellular senescence in tendon. These insights highlight AMPK signaling as a promising therapeutic target and underscore the beneficial role of exercise in mitigating tendinopathic changes.

pathology↗