Sex-specific differences in motor unit remodeling in a mouse model of ALS

Abstract

Progressive loss of neuromuscular junctions (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), preceding the global degeneration of motor axons and being accompanied by new axonal sprouting within the same axonal arbor. Some aspects of ALS onset and progression seem to be affected by sex in animal models of the disease. However, whether there are sex-specific differences in the pattern or time course of NMJ loss and repair within single motor axons remains unknown. We performed further analysis of a previously published in vivo dataset, obtained from male and female SOD1^G37R mice. We found that NMJ losses are as frequent in male and female motor axons but, intriguingly, axonal sprouting is more frequent in female than male mice, resulting in a net increase of axonal arborization. Interestingly, these numerous new axonal branches in female mice are associated with a slightly faster decline in grip strength, increased NMJ denervation, and reduced α-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motor-unit expansion in female SOD1^G37R mice are maladaptive during ALS progression.

Significance Statement Sex-specific differences in ALS progression have been identified in patients and in some animal models of the disease. However, the physio-pathological changes underlying these disparities remain poorly defined. In this study, we identified that the pattern of motor axon retraction and regrowth in skeletal muscles is a novel factor to consider in our understanding of sex-linked differences in ALS. Analysis of single motor axons in a model of ALS identified that female motor axons were more likely to form compensatory branches, which was associated with a worse phenotype. These surprising findings highlight the necessity to more systematically evaluate the prevalence of sex-specific differences across animal models of ALS and in patients.