Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Abstract

Progressive loss of neuromuscular junctions (NMJs) 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 a-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motorunit (MU) expansion in female SOD1 G37R mice are maladaptive during ALS progression.Sex-specific differences in amyotrophic lateral sclerosis (ALS) progression have been identified in patients and in some animal models of the disease. However, the physio-pathologic 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.

Boosting The Peripheral Immune Response in the Skeletal Muscles Improved Motor Function in ALS Transgenic Mice

“…3A, B). Altogether these data align with previous evidence suggesting maladaptive axonal sprouting in mSOD1 mice as the disease progresses [76,77].…”

Sex-dependent effects of amyloid precursor-like protein 2 in the SOD1-G37R transgenic mouse model of MND

“…This increased incidence in the male population is in line with the majority of epidemiological studies showing male MND patients tend to show an earlier age of disease onset [87], an effect that is also recapitulated in selective transgenic mouse models of MND [88,89]. Although sex-specific differences have been identified in both the SOD1-G37R [90] and the SOD1-G93A mouse models for MND [15,16,18], our new findings identified sex-dependent effect associated with APP and APLP2 expression levels which may be linked to their neuroprotective properties in neurodegenerative disorders. Nevertheless, further clinical studies are needed to clarify the specifics of these sex differences involving SOD1 in MND and how APP and APLP2 contributes to this.…”

Amyotrophic Lateral Sclerosis Survival Associates With Neutrophils in a Sex-specific Manner

“… 41 Another study showed that axonal sprouting varies between male and female SOD1 G37R mice. 42 A more recent prospective study found that prediagnostic eosinophil levels associated with ALS risk differently in males and females. 43 Finally, low-density lipoprotein–related receptor protein 4 antibodies are more commonly detected in female vs male ALS participants.…”