Molecular changes in transcription and metabolic pathways underlying muscle atrophy in the CuZnSOD null mouse model of sarcopenia

Autor: Willard M. Freeman, Kaitlyn Street, Michael Kinter, Caroline S. Kinter, Jonathan D. Wren, Rojina Ranjit, Katarzyna M. Piekarz, Arlan Richardson, Holly Van Remmen, Constantin Georgescu, Jacob L. Brown, Gavin Pharaoh, Kavithalakshmi Sataranatarajan
Rok vydání: 2020
Předmět:
Zdroj: GeroScience
ISSN: 2509-2723
2509-2715
DOI: 10.1007/s11357-020-00189-x
Popis: Mice lacking the superoxide anion scavenger CuZn superoxide dismutase (Sod1(−/−) mice) develop a number of age-related phenotypes, including an early progression of muscle atrophy and weakness (sarcopenia) associated with loss of innervation. The purpose of this study was to delineate the early development of sarcopenia in the Sod1(−/−) mice and to measure changes in the muscle transcriptome, proteome, and eicosanoid profile at the stage when sarcopenia is markedly induced in this model (7–9 months of age). We found a strong correlation between muscle atrophy and mitochondrial state 1 hydroperoxide production, which was 40% higher in isolated mitochondria from Sod1(−/−) mouse gastrocnemius muscle by 2 months of age. The primary pathways showing altered gene expression in Sod1(−/−) mice identified by RNA-seq transcriptomic analysis are protein ubiquitination, synaptic long-term potentiation, calcium signaling, phospholipase C signaling, AMPK, and TWEAK signaling. Targeted proteomics shows elevated expression of mitochondrial proteins, fatty acid metabolism enzymes, tricarboxylic acid (TCA) cycle enzymes, and antioxidants, while enzymes involved in carbohydrate metabolism are downregulated in Sod1(−/−) mice. LC-MS analysis of lipids in gastrocnemius muscle detected 78 eicosanoids, of which 31 are significantly elevated in muscle from Sod1(−/−) mice. These data suggest that mitochondrial hydroperoxide generation is elevated prior to muscle atrophy and may be a potential driving factor of changes in the transcriptome, proteome, and eicosanoid profile of the Sod1(−/−) mice. Together, these analyses revealed important molecular events that occur during muscle atrophy, which will pave the way for future studies using new approaches to treat sarcopenia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00189-x) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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