Research Paper Volume 15, Issue 2 pp 308—352

Body weight influences musculoskeletal adaptation to long-term voluntary wheel running during aging in female mice

Yukiko Kitase1, *, , Julian A. Vallejo2,5, *, , Sarah L. Dallas2, , Yixia Xie2, , Mark Dallas2, , LeAnn Tiede-Lewis2, , David Moore2, , Anthony Meljanac2, , Corrine Kumar1, , Carrie Zhao1, , Jennifer Rosser2, , Marco Brotto3, , Mark L. Johnson2, , Ziyue Liu4, , Michael J. Wacker5, , Lynda Bonewald6, ,

  • 1 Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
  • 2 Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri, Kansas City, MO 64108, USA
  • 3 Bone-Muscle Research Center, College of Nursing and Health Innovation, University of Texas, Arlington, TX 76019, USA
  • 4 Department of Biostatistics and Health Data Science, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
  • 5 Department of Biomedical Sciences, School of Medicine, University of Missouri, Kansas City, MO 64108, USA
  • 6 Department of Orthopaedic Surgery, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
* Shared first authorship

Received: July 21, 2022       Accepted: November 2, 2022       Published: November 18, 2022
How to Cite

Copyright: © 2022 Kitase et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Frailty is the hallmark of aging that can be delayed with exercise. The present studies were initiated based on the hypothesis that long-term voluntary wheel running (VWR) in female mice from 12 to 18 or 22 months of age would have beneficial effects on the musculoskeletal system. Mice were separated into high (HBW) and low (LBW) body weight based on final body weights upon termination of experiments. Bone marrow fat was significantly higher in HBW than LBW under sedentary conditions, but not with VWR. HBW was more protective for soleus size and function than LBW under sedentary conditions, however VWR increased soleus size and function regardless of body weight. VWR plus HBW was more protective against muscle loss with aging. Similar effects of VWR plus HBW were observed with the extensor digitorum longus, EDL, however, LBW with VWR was beneficial in improving EDL fatigue resistance in 18 mo mice and was more beneficial with regards to muscle production of bone protective factors. VWR plus HBW maintained bone in aged animals. In summary, HBW had a more beneficial effect on muscle and bone with aging especially in combination with exercise. These effects were independent of bone marrow fat, suggesting that intrinsic musculoskeletal adaptions were responsible for these beneficial effects.


VWR: Voluntary wheel running; HBW: High body weight; LBW: Low body weight; CBW: Combined body weight; CTRL: Control; BMAT: Bone marrow adipose tissue; TA: Total area; BW: Body weight; HW: Heart weight; MW: Muscle weight; EDL: Extensor digitorum longus; SOL: Soleus; CSA: Cross-sectional area; MyHC: myosin heavy chain; CM: Conditioned media; BMD: Bone mineral density; BV/TV: bone volume; Co.Th: cortical thickness; Co.Area: cortical area; Pe.Cir: periosteal circumference; En.Cir: endosteal circumference; Tb.Th: Trabecular thickness; Tb.Sp: Trabecular separation; Tb.N: Trabecular number; Conn.D: Connectivity density; WTF: Work to failure; ROS: Reactive oxygen species; ATP: Adenine triphosphate; L-BAIBA: L-β-aminoisobutyric acid; MRGPRD: Mas-related G-protein coupled receptor, type D; PBS: Phosphate-buffered saline; MMA: methyl methacrylate; FBS: Fetal bovine serum; CS: calf serum; EDTA: Ethylenediaminetetraacetic Acid; DAPI: 4’,6-diamidino-2-phenylindole; TUNEL: TdT-mediated dUTP nick-end labeling; ANOVA: analysis of variance.