Upregulation of Mitofusin2 in neurons slows down skeletal muscles atrophy in ALS disease and aging model

Abstract

Skeletal muscles undergo atrophy in response to diseases and aging. Mitochondria, the source of cellular energy, were found to be fragmented in experimental models of ALS disease and aging. However, whether and how mitochondrial fragmentation plays a role in the progression of disease and aging is not clear. Mitofusin2 (Mfn2) is a key regulator of mitochondrial fusion which is crucial for the maintenance of mitochondrial morphology. To test whether Mfn2 reduction in motor neurons contributed to the disease progression in SOD1G93A mice or aged mice, we generated transgenic mice overexpressing Mfn2 specifically in neurons under the control of the Thy1.2 promoter (TMFN mice). Mfn2 overexpression was confirmed in spinal cords but not skeletal muscles. By crossing Mfn2 overexpressed mice with SOD1G93A mice, we obtained double transgenic Mfn2/SOD1G93A mice. Interestingly, mitochondrial fragmentation was abolished in motor neurons of Mfn2/SOD1G93A mice even in the disease endstage. Strikingly, characteristic neuromuscular junction (NMJ) denervation, collapse, and dysfunction in SOD1G93A mice were also greatly alleviated in Mfn2/SOD1G93A mice. The dramatic protective effect of neuronal Mfn2 in SOD1G93A mice was further indicated by the greatly delayed symptom onset of more than 60 days and the complete prevention of behavioral deficits at 120 days old, a very late stage immediately before endstage onset.A similar protective effect was observed in aged mice. The Mfn2 neuronal overexpression mice suffered less neuromuscular synaptic dysfunction and skeletal muscle atrophy than their non‐transgenic litter mates even at 22 months old, which in human years is equivalent to the 70s. Taken together, our study provides evidence suggesting that Mfn2 deficiency induced mitochondrial fragmentation in motor neurons is likely an important mechanism leading to NMJ dysfunction and skeletal muscle atrophy in ALS and aging, and that Mfn2 could be a common therapeutic target for skeletal muscle atrophy.Support or Funding InformationThis study is supported by grants from the US NIH (1R01NS097679 and 1R01NS089604), US Alzheimer's Association (AARG‐17‐499682), and US Association for Frontotemporal Degeneration and Alzheimer's Drug Discovery Foundation (20161206).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.