CuZnSOD expressed specifically in neurons rescues mitochondrial function and calcium handling in muscles of Sod1KO mice

Abstract

BackgroundAging is accompanied by loss of muscle mass and force. The mechanism of the loss is not fully understood, but oxidative stress and mitochondrial dysfunction have been implicated as potential contributors. Mice deficient in CuZnSOD (Sod1−/− mice) show decreased ATP production and increased generation of reactive oxygen species by muscle mitochondria as well as muscle atrophy and weakness early in life that is reminiscent of that observed in old age in wild type (WT) mice. Thus, Sod1−/− mice represent a model of accelerated neuromuscular aging. Surprisingly, SynTgSod1−/− mice, which have Sod1 expression restored specifically in neurons, show none of the neuromuscular deficits observed in Sod1−/− mice. To investigate how neuron‐specific Sod1 expression rescues muscle mass and force in Sod1−/− mice, we examined contractile properties and mitochondrial function in muscles of SynTgSod1−/− mice.MethodLumbrical muscles were removed from 7–9 months old wild‐type, Sod1−/−, and SynTgSod1−/− mice, attached to a force transducer, and placed in an experimental chamber for the measurement of muscle contractile parameters and NADH fluorescence was recorded as a measure of mitochondrial redox status. Because mitochondrial function is regulated by calcium, we also examined intracellular calcium transients (ICT) using the fluorescent dye Mag‐fura2. Immunofluorescence techniques were used to examine neuromuscular junction (NMJ) structure and fiber type composition.ResultCompared with WT muscles, mitochondria of muscles of Sod1−/− mice were in a more reduced state at rest and became transiently more oxidized following a 5s maximum isometric contraction. Consistent with the idea that recovery of NADH may be driven by calcium activation of the TCA cycle, the peak of the ICT was reduced and the width prolonged in muscles of Sod1−/− mice. For all measures, muscles of SynTgSod1−/− and WT mice were not different. A shift in muscle fiber type composition observed in Sod1−/− mice was also restored in SynTgSod1−/− mice. Moreover, NMJ denervation and fragmentation was rescued in SynTg Sod1−/− mice.ConclusionOur finding of improved mitochondrial function in muscles of SynTgSod1−/− compared with Sod1−/− mice is consistent with the hypothesis that the mitochondrial dysfunction is an important contributor to the development of atrophy and weakness in Sod1−/− mice. Since SynTgSod1−/− mice are still lacking CuZnSOD in muscle, we conclude that appropriate neuronal function and intact innervation are key to maintaining muscle mitochondrial function and overall muscle size and strength.Support or Funding InformationSupported by NIH Grant AG051442 and the Second Xiangya Hospital of Central South University, ChinaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.