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Free Radic Biol Med. 2019 Feb 20;132:19-23. doi: 10.1016/j.freeradbiomed.2018.06.032. Epub 2018 Jul 2.

Accelerated sarcopenia in Cu/Zn superoxide dismutase knockout mice.

Author information

1
Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA.
2
Aging and Metabolism Division, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Oklahoma City VA Medical Center, Oklahoma City, OK, USA.
3
Department of Molecular and Integrative Physiology University of Michigan, Ann Arbor, MI, USA.
4
Department of Molecular and Integrative Physiology University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering University of Michigan, Ann Arbor, MI, USA.
5
Department of Musculoskeletal Biology, MRC Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
6
Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA; Oklahoma City VA Medical Center, Oklahoma City, OK, USA. Electronic address: Arlan-richardson@ouhsc.edu.

Abstract

Mice lacking Cu/Zn-superoxide dismutase (Sod1-/- or Sod1KO mice) show high levels of oxidative stress/damage and a 30% decrease in lifespan. The Sod1KO mice also show many phenotypes of accelerated aging with the loss of muscle mass and function being one of the most prominent aging phenotypes. Using various genetic models targeting the expression of Cu/Zn-superoxide dismutase to specific tissues, we evaluated the role of motor neurons and skeletal muscle in the accelerated loss of muscle mass and function in Sod1KO mice. Our data are consistent with the sarcopenia in Sod1KO mice arising through a two-hit mechanism involving both motor neurons and skeletal muscle. Sarcopenia is initiated in motor neurons leading to a disruption of neuromuscular junctions that results in mitochondrial dysfunction and increased generation of reactive oxygen species (ROS) in skeletal muscle. The mitochondrial ROS generated in muscle feedback on the neuromuscular junctions propagating more disruption of neuromuscular junctions and more ROS production by muscle resulting in a vicious cycle that eventually leads to disaggregation of neuromuscular junctions, denervation, and loss of muscle fibers.

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