Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder stemming from deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased levels of SMN protein, and subsequent motor neuron death and muscle atrophy. While traditionally viewed as a disorder predominantly affecting motor neurons, recent research suggests the involvement of various peripheral organs in SMA pathology. Notably, the liver has emerged as a significant focus due to the observed fatty liver phenotype and dysfunction in both SMA mouse models and SMA patients. Despite these findings, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this knowledge gap, we developed a mouse model with a liver-specific depletion of SMN by utilizing an Alb-Cre transgene together with one Smn2B allele and one Smn exon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), a time when the severe model of SMA, the Smn2B/-mice, typically exhibit many symptoms of the disease. Our findings indicate that liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the Smn2B/- mouse at P19. However, mild liver steatosis was observed at this time point, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of Smn2B/-mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producing α-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1) levels. Moreover, these changes were transient, as P60 mice exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA, adding a nuanced layer to our understanding of the disease’s complexities.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Note that the title has been slightly modified as per the suggestion of one of the reviewers. We have carefully addressed the reviewers' constructive feedback and believe the revisions significantly enhance both the clarity and impact of the manuscript. In this revised version, we have meticulously incorporated all textual suggestions, corrected minor typographical errors, and updated the manuscript with the most recent relevant literature. One of the key improvements is the extension of our analysis to include P60 mice. This new data explores the progression of the phenotype in liver-specific SMN-depleted mice over time, providing insights into whether the observed pathologies worsen or improve. We also expanded our study to include both liver and pancreatic assessments at this later time point. Additionally, we now present a comprehensive analysis of metabolic hormone levels related to glucose metabolism at both P19 and P60, along with new figures that not only enrich the manuscript's novelty but also deepen our understanding of the model. Furthermore, we have provided a detailed characterization of Cre expression in the liver, pancreas, and spinal cord (SC) at P19, and in the liver at P60. This confirms Cre-specific expression in the liver and reveals a variable pattern of expression across hepatocytes, consistent with prior expectations. Our revised manuscript also introduces new findings regarding elevated plasma glucagon and glucagon-like peptide (GLP-1) levels in liver-specific SMN-depleted mice, aligning with histological evidence of pancreatic dysfunction. Interestingly, these effects appear to be transient, likely due to the stochastic nature of Cre expression and the dynamic regenerative capacity of hepatocytes.
