ADSS1 myopathy is a rare autosomal recessive distal myopathy caused by mutations in the ADSS1 gene, which encodes a muscle-specific enzyme critical for the purine nucleotide cycle (PNC). The cellular mechanisms underlying ADSS1-related myopathy remain unknown, and no treatments exist.
We acquired 6 iPSC lines, including two ADSS1 myopathy siblings and a non-diseased familial control, an isogenic variant derived from healthy control and an independent healthy control. One ADSS1 and one control iPSC line were selected for skeletal muscle differentiation following our iMyoblast protocol combining iPS primary myogenic iMyocyte differentiation and reserve cell isolation of adult-like iMyoblasts.
Preliminary data establish that ADSS1 iPSCs undergo primary iMyocyte differentiation but have reduced expression of PNC genes in differentiated primary iMyocytes similar to observations reported in muscle biopsies of ADSS1 patients. However, ADSS1 iMyoblasts express higher levels of myostatin and have reduced growth and expression of myogenic markers. These preliminary findings indicate that iPSC derived myogenic cells can model ADSS1 disruption of PNC gene expression in primary iMyocytes and suggest that ADSS1 is required for iMyoblast myogenesis and identify myostatin as a biomarker of ADSS1 pathology.
Upcoming experiments will compare the differentiation of primary iMyocytes and adult-like iMyoblast differentiation in the cohort of ADSS1 and control iPSC lines using RNAseq as well as investigate metabolic defects associated with ADSS1 pathology using metabolomics assays. By integrating transcriptional and metabolic findings, this project will advance understanding of ADSS1 myopathy, identify diagnostic biomarkers, and develop therapeutic strategies. Findings will also provide insights into mechanisms underlying the pathology of PNC-related muscular and metabolic disorders.
We thank Cure ADSSL1 for providing patient iPSC lines.