Transgenic expression of SOD1 specifically in neurons of Sod1 deficient mice prevents defects in muscle mitochondrial function and calcium handling.

Abstract

Aging is accompanied by loss of muscle mass and force, known as sarcopenia. Muscle atrophy, weakness, and neuromuscular junction (NMJ) degeneration reminiscent of normal muscle aging are observed early in adulthood for mice deficient in Cu, Zn-superoxide dismutase (SOD, Sod1-/-). Muscles of Sod1-/- mice also display impaired mitochondrial ATP production and increased mitochondrial reactive oxygen species (ROS) generation implicating oxidative stress in sarcopenia. Restoration of CuZnSOD specifically in neurons of Sod1-/- mice (SynTgSod1-/-) prevents muscle atrophy and loss of force, but whether muscle mitochondrial function is preserved is not known. To establish links among CuZnSOD expression, mitochondrial function, and sarcopenia, we examined contractile properties, mitochondrial function and ROS production, intracellular calcium transients (ICT), and NMJ morphology in lumbrical muscles of 7-9 month wild type (WT), Sod1-/-, and SynTgSod1-/- mice. Compared with WT values, mitochondrial ROS production was increased 2.9-fold under basal conditions and 2.2-fold with addition of glutamate and malate in Sod1-/- muscle fibers while oxygen consumption was not significantly altered. In addition, NADH recovery was blunted following contraction and the peak of the ICT was decreased by 25%. Mitochondrial function, ROS generation and calcium handling were restored to WT values in SynTgSod1-/- mice, despite continued lack of CuZnSOD in muscle. NMJ denervation and fragmentation were also fully rescued in SynTgSod1-/- mice suggesting that muscle mitochondrial and calcium handling defects in Sod1-/- mice are secondary to neuronal oxidative stress and its effects on the NMJ rather than the lack of muscle CuZnSOD. We conclude that intact neuronal function and innervation are key to maintaining excitation-contraction coupling and muscle mitochondrial function.

• Authors: Yu Su, Bumsoo Ahn, Peter C D Macpherson, Rojina Ranjit, Dennis R Claflin, Holly Van Remmen, Susan V Brooks
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 165 Pg. 299-311 (03 2021) ISSN: 1873-4596 [Electronic] United States
• PMID: 33561489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Sod1 protein, mouse
• Superoxide Dismutase
• Superoxide Dismutase-1
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria
• Muscle, Skeletal (metabolism)
• Neurons (metabolism)
• Superoxide Dismutase (genetics, metabolism)
• Superoxide Dismutase-1 (genetics, metabolism)