Reassessing the role of progenitor cells in muscle wasting in cancer cachexia

Skeletal muscles contain myogenic and nonmyogenic progenitor cells that proliferate and differentiate after tissue damage to restore myofiber, connective tissue, and blood vessel homeostasis. We previously showed that cancer-induced muscle wasting involves myofiber damage and impaired differentiation of myogenic progenitors, coincident with the aberrant accumulation of mesenchymal progenitor cells expressing both myogenic (Pax7) and nonmyogenic (Sca1, Pdgfrα) progenitor markers. Here, we combined lineage tracing and scRNA-seq to more deeply explore muscle resident progenitor cells during cancer cachexia. Colon-26 (C-26) carcinoma cells were injected into adult (≥12-wk-old) Pax7-Cre^ER; Rosa26-LSL-tdTomato mice, and tamoxifen was administered after tumors were established but before cachexia. At cachexia endpoint, scRNA-seq analysis was performed on muscle mononuclear cells. In both control and C-26 muscles, Pax7 and tdTomato transcripts were restricted to myogenic progenitors, whereas Sca1 and Pdgfrα were restricted to nonmyogenic progenitors. These results were confirmed by flow cytometry and suggest that mesenchymal progenitor cells do not commit to a myogenic fate during cancer cachexia. However, consistent with earlier findings, our transcriptomic analyses validated that myogenic progenitors from tumor-bearing mice were impaired in differentiating. When we repeated Pax7-lineage tracing and scRNA-seq on young mice (6-wk-old) still undergoing developmental muscle growth, similar results were obtained, but interestingly, by flow cytometry, we detected a small population of Sca1⁺; tdTomato⁺ cells, not present in adult muscles. Thus, nonmyogenic progenitors might indeed be capable of adopting a myogenic fate during cancer cachexia, but this contributes to only a minor fraction of Pax7⁺ cells and is likely to be age-dependent.NEW & NOTEWORTHY Here, we performed Pax7-lineage tracing and unbiased scRNA-seq on skeletal muscle mononuclear cells during cancer cachexia. We found myogenic progenitors from cachectic muscle have an activation-like transcriptional profile, with concurrent downregulation of terminal differentiation genes. However, contrary to previous findings, aberrant commitment of nonmyogenic progenitors to a myogenic lineage did not occur in cachectic muscle. Subsequent experiments demonstrated that inflammation and impaired differentiation of activated myogenic progenitors occur early in tumor progression, before muscle wasting.