Elucidating the role of xanthine oxidoreductase in regulating muscle dysfunction in cancer cachexia

About This Grant

PROJECT SUMMARY Cancer cachexia involves the accelerated loss of skeletal muscle mass and function which significantly reduce patient treatment options, quality of life, and survival time. In addition to atrophy of myofibers, ectopic accumulation of adipocytes between and within muscle tissues, generally referred to as myosteastosis, is a distinguishing feature of muscle degeneration during cancer and its comorbidities which independently predicts poor muscle function and prognosis. However, the exact mechanisms regulating myosteatosis during cancer, and their relevance to muscle wasting, are unknown. Adipocyte formation in skeletal muscle is indicated to result from the adipogenesis of a population of mesenchymal stem cells known as fibro-adipogenic progenitor cells (FAPs) that reside in the muscle tissue microenvironment. Preliminary experiments using mouse models of cancer cachexia and single-cell RNA sequencing revealed that muscles from tumor-bearing mice had more adipocytes than non-tumor bearing controls, which coincided with an increase in FAPs expressing adipogenesis promoting genes. One of the top-most upregulated genes in FAPs from cachectic muscle encodes the enzyme xanthine oxidoreductase (XOR) which is known to be essential for adipogenesis in vitro and in vivo. XOR is also known to be a major source of reactive oxygen species production that can activate NF-B, a transcription factor that promotes muscle wasting during cancer cachexia. Therefore, this proposal will seek to elucidate the role of XOR in FAPs to myosteatosis and muscle dysfunction during cancer cachexia. In Aim 1, multiple mouse models of cancer cachexia will be used, in combination with Pdgfrα-CreER; tdTomato and XORfl/fl mice, to determine if cancer promotes FAP adipogenesis through a XOR-dependent mechanism. In Aim 2, in vitro and in vivo experiments will be conducted to determine if increased XOR activity in FAPs contributes to NF-B activation in muscles during cancer cachexia.