50 - Inducible motor neuron specific deletion of CuZn Superoxide dismutase accelerates muscle atrophy in mice

Abstract

Age-associated loss of muscle mass and function has a profound effect on the quality of life in elderly people, yet the mechanisms are unknown and treatments are lacking. Our previous studies have shown that absence of CuZn superoxide dismutase in mice (Sod1KO mice) is associated with a number of characteristics of the sarcopenia phenotype including elevated oxidative stress, mitochondrial dysfunction, accelerated age-associated muscle atrophy and weakness and neuromuscular denervation suggesting oxidative stress and loss of innervation play a key role in initiating muscle atrophy and weakness in aging. Interestingly, neuron specific rescue of CuZnSOD in Sod1KO mice rescued these phenotypes supporting an important role for motor neuron deficits in the etiology of sarcopenia. Here we hypothesized that motor neuron-specific reduction of Sod1 would be sufficient to induce muscle atrophy. To test this, we generated inducible motor neuron-specific Sod1 knock out mice (i-mnSod1KO mice) using motor neuron specific SlickH Cre mice bred to mice carrying a floxed Sod1 allele. Mice were injected at 4 months of age with tamoxifen (2.5 mg/kg body weight) for 3 days and sacrificed at ten months of age. The i-mnSod1KO mice showed a reduction in CuZnSOD protein expression in brain (61.4%), spinal cord (73.4%) and sciatic nerve (60%), but skeletal muscle CuZnSOD expression was not changed. Motor neuron number (28%) and area (48.1%) and protein expression of choline acetyl transferase (ChAT) are reduced in sciatic nerve of i-mnSod1KO mice and neuromuscular junctions showed increased NMJ fragmentation (31%). Gastrocnemius muscle showed markers of muscle denervation (acetylcholine alpha, delta, GADD45 alpha, and RUNX) and muscle atrophy (MURF1) in i-mnSod1KO mice and muscle mass was reduced approximately 23.3% (p>0.004). In contrast to our previous findings in the Sod1KO mice, mitochondrial function is not altered in gastrocnemius muscle in response to the neuronal deletion of Sod1. In summary, our findings suggest that elevated oxidative stress in the motor neuron alone can cause muscle atrophy in mice and point to neuronal deficits as causal in age related loss of muscle mass.