Mitochondrial Function Is Compromised in Cortical Bone Osteocytes of Long-Lived Growth Hormone Receptor Null Mice

Zhongbo Liu, Maria E. Solesio, Mitchell B. Schaffler, Dorra Frikha-Benayed, Clifford J. Rosen, Haim Werner, John J. Kopchick, Evgeny V. Pavlov, Andrey Y. Abramov, Shoshana Yakar

Research output: Contribution to journalArticle

Abstract

Despite increased longevity and resistance to multiple stressors, growth hormone receptor null (GHRKO) mice exhibit severe skeletal impairment. The role of GHR in maintaining osteocyte mitochondrial function is unknown. We found that GHR ablation was detrimental to osteocyte mitochondrial function. In vivo multiphoton microscopy revealed significant reductions of >10% in mitochondrial membrane potential (MMP) in GHRKO osteocytes and reduced mitochondrial volumetric density. Reductions in MMP were accompanied by reductions in glucose transporter-1 levels, steady state ATP, NADH redox index, oxygen consumption rate, and mitochondrial reserve capacity in GHRKO osteocytes. Glycolytic capacity did not differ between control and GHRKO males’ osteocytes. However, osteocytes from aged female GHRKO mice exhibited reductions in glycolytic parameters, indicating impairments in glucose metabolism, which may be sex dependent. GHRKO osteocytes exhibited increased levels of cytoplasmic reactive oxygen species (ROS) (both basal and in response to high glucose), insulin-like growth factor-1 (IGF-1), and insulin. Mitochondrial ROS levels were increased and correlated with reduced glutathione in GHRKO osteocytes. Overall, the compromised osteocyte mitochondrial function and responses to metabolic insults strongly correlated with skeletal impairments, suggesting that despite increased life span of the GHRKO mice, skeletal health span is decreased.

Original languageEnglish (US)
Pages (from-to)106-122
Number of pages17
JournalJournal of Bone and Mineral Research
Volume34
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • GROWTH HORMONE
  • NADH REDOX
  • OSTEOCYTE
  • REACTIVE OXYGEN SPECIES
  • RESPIRATION

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Liu, Z., Solesio, M. E., Schaffler, M. B., Frikha-Benayed, D., Rosen, C. J., Werner, H., Kopchick, J. J., Pavlov, E. V., Abramov, A. Y., & Yakar, S. (2019). Mitochondrial Function Is Compromised in Cortical Bone Osteocytes of Long-Lived Growth Hormone Receptor Null Mice. Journal of Bone and Mineral Research, 34(1), 106-122. https://doi.org/10.1002/jbmr.3573