Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice

Bhaskaran, Shylesh, Pollock, Natalie ORCID: 0000-0002-4969-5486, Macpherson, Peter C, Ahn, Bumsoo, Piekarz, Katarzyna M, Staunton, Caroline A ORCID: 0000-0003-0647-3063, Brown, Jacob L, Qaisar, Rizwan, Vasilaki, Aphrodite ORCID: 0000-0002-5652-0895, Richardson, Arlan
et al (show 4 more authors) (2020) Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice. AGING CELL, 19 (10). e13225-.

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Age-associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice (Sod1<sup>-/-</sup> mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2- to 4-month-old) Sod1flox/SlickHCre mice with tamoxifen to generate i-mn-Sod1KO mice. CuZnSOD protein was 40-50% lower in neuronal tissue in i-mn-Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18- to 22-month-old i-mn-Sod1KO mice. By 24 months, 22% of NMJs in i-mn-Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal-specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.

Item Type: Article
Uncontrolled Keywords: aging, CuZnSOD, denervation, motor neuron, sarcopenia
Depositing User: Symplectic Admin
Date Deposited: 01 Oct 2020 09:01
Last Modified: 18 Jan 2023 23:30
DOI: 10.1111/acel.13225
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