Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and NMJs associated with premature muscle atrophy in aging mice

摘要: Whole body knock out of Cu, Zn superoxide dismutase1 (Sod1KO) results in accelerated, age-related loss of muscle mass and function associated with a breakdown of neuromuscular junctions (NMJ) similar to sarcopenia. In order to determine whether altered redox in motor neurons is integral to this phenotype, an inducible neuron specific deletion of Sod1 (i-mnSod1KO) was compared with wild type (WT) mice of different ages (adult, mid-age and old) and whole body Sod1KO mice. Nerve oxidative damage, motor neuron numbers and structural changes to neurons and NMJ were examined.Deletion of neuronal Sod1 (induced by tamoxifen injection at 6 months of age) caused the exaggerated, age-associated loss of muscle mass and force generation previously reported. No effect of age or lack of neuronal Sod1 was seen on oxidation in the sciatic nerve assessed by electron paramagnetic resonance of the in vivo spin probe 1-hydroxy-3-carboxy-2,2,5,5 tetramethylpyrrolidine (CPH), analysis of protein 3-nitrotyrosines or carbonyl content. i-mnSod1KO mice showed increased numbers of denervated NMJs, a reduced number of large axons and increased number of small axons compared with age-matched old WT mice. A large proportion of the remaining innervated NMJs in i-mnSod1KO mice also displayed a much simpler structure than that seen in WT mice.Thus, while Sod1KO mice recapitulate substantially the neuromuscular phenotypes of old WT mice, deletion of Sod1 specifically in neurons induces exaggerated loss of muscle mass and force only in old (24-29 month) mice indicating that significant muscle declines require the …