Comparison of Whole Body SOD1 Knockout with Muscle-Specific SOD1 Knockout Mice Reveals a Role for Nerve Redox Signaling in Regulation of Degenerative Pathways in Skeletal Muscle

Sakellariou, Giorgos K.; McDonagh, Brian; Porter, Helen; Giakoumaki, Ifigeneia I.; Earl, Kate E.; Nye, Gareth A.; Vasilaki, Aphrodite; Brooks, Susan V.; Richardson, Arlan; Van Remmen, Holly; McArdle, Anne; Jackson, Malcolm J.

Abstract

Aims: Lack of Cu,Zn-superoxide dismutase (CuZnSOD) in homozygous knockout mice (Sod1−/−) leads to accelerated age-related muscle loss and weakness, but specific deletion of CuZnSOD in skeletal muscle (mSod1KO mice) or neurons (nSod1KO mice) resulted in only mild muscle functional deficits and failed to recapitulate the loss of mass and function observed in Sod1−/− mice. To dissect any underlying cross-talk between motor neurons and skeletal muscle in the degeneration in Sod1−/− mice, we characterized neuromuscular changes in the Sod1−/− model compared with mSod1KO mice and examined degenerative molecular mechanisms and pathways in peripheral nerve and skeletal muscle.

Results: In contrast to mSod1KO mice, myofiber atrophy in Sod1−/− mice was associated with increased muscle oxidative damage, neuromuscular junction degeneration, denervation, nerve demyelination, and upregulation of proteins involved in maintenance of myelin sheaths. Proteomic analyses confirmed increased proteasomal activity and adaptive stress responses in muscle of Sod1−/− mice that were absent in mSod1KO mice. Peripheral nerve from neither Sod1−/− nor mSod1KO mice showed increased oxidative damage or molecular responses to increased oxidation compared with wild type mice. Differential cysteine (Cys) labeling revealed a specific redox shift in the catalytic Cys residue of peroxiredoxin 6 (Cys47) in the peripheral nerve from Sod1−/− mice.

Innovation and Conclusion: These findings demonstrate that neuromuscular integrity, redox mechanisms, and pathways are differentially altered in nerve and muscle of Sod1−/− and mSod1KO mice. Results support the concept that impaired redox signaling, rather than oxidative damage, in peripheral nerve plays a key role in muscle loss in Sod1−/− mice and potentially sarcopenia during aging. Antioxid. Redox Signal. 28, 275–295.

• Journal Article Type: Article
• Acceptance Date: Aug 31, 2017
• Publication Date: Feb 1, 2018
• Deposit Date: Jan 24, 2025
• Journal: Antioxidants & Redox Signaling
• Print ISSN: 1523-0864
• Electronic ISSN: 1557-7716
• Publisher: Mary Ann Liebert
• Peer Reviewed: Peer Reviewed
• Volume: 28
• Issue: 4
• Pages: 275-295
• DOI: https://doi.org/10.1089/ARS.2017.7249