Fig. 5. Cachexia caused by a pediatric melanoma xenograft induces myofiber atrophy in the diaphragm.

a–p Analysis of myofiber size in diaphragm muscles of mice undergoing wasting at 2 a–d, 4 e–h, 6 i–l, and 8 m–p weeks post implantation of a cachexia-inducing (“cachectic”) melanoma xenograft, compared to a cachexia-non-inducing (“non-cachectic”) melanoma xenograft or mock injection of PBS (n = 5/group). At the early stages of cachexia progression (2-4 weeks), there is no substantial decline in myofiber size, as indicated by the analysis of the Feret’s minimal diameter a–b, e–f. At later stages (6–8 weeks), there is a trend towards a decline in the size of type 1, 2a, and 2x/2b myofibers at 6 weeks of age i, j, l, which however is significant only after 8 weeks from cancer cell injection m, n, p. There are no changes in the relative proportion of myofiber types found in diaphragm muscles c, g, o, apart for a slight increase in type 2x/2b myofibers at 6 weeks (k). Mean values ± SD are shown in panels b–c, f–g, j–k, and n–o. Statistical analysis was done by using two-way ANOVA with Sidak’s multiple comparisons test. q Heatmap of 1033 genes that are most highly modulated by melanoma-induced cachexia in the diaphragm, compared to controls. r Upregulated genes include secreted proteins, proteins involved in innate immunity and neutrophil chemotaxis, and metalloprotease inhibitors. s Downregulated genes are also enriched for secreted and extracellular matrix proteins. Genes modulated with P < 0.05 and Log2R > 1 r and Log2R < -1 s in cachectic versus control at 8 weeks post tumor implantation are shown. Source data are provided in the Source Data file.