Multi-tissue spatial transcriptomics identified simultaneous responses to oxidative stress and apoptosis in parallel with tissue-specific reprogramming in modeled chronic kidney disease-mineral and bone disorder.

Musculoskeletal dysfunction in chronic kidney disease-mineral and bone disorder (CKD-MBD) is associated with morbidity and mortality. Disease alterations in bone and muscle, and among muscle fiber types, have largely been tested by candidate gene analysis in individual tissues. We undertook a multi-tissue spatial transcriptomics (ST) approach to identify and differentiate tissue-specific and -common genomic reprogramming occurring simultaneously in cortical bone, muscle, and marrow during CKD-MBD. Visium ST was used on femur-muscle histological cross sections from male mice with adenine diet-induced CKD-MBD (0.2%; 4 wk), or casein control diet. The spatial sequencing datasets were analyzed for differential gene expression and pathway analyses. Transcriptional changes were validated using qPCR in the contralateral tissues as well as in the original sections. Uniform manifold approximation and projection analyses paired with hallmark transcript mapping distinguished cortical bone and bone marrow, slow vs. fast twitch muscle fiber cell populations, including 3 fast twitch muscle subtypes (IIa, IIx, and IIb). Upregulation of apoptosis and oxidative stress pathways, including genes