Fig. 7
From: Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice
Increasing Tweak activity via Fc-TWEAK improves disease phenotypes in two SMA mouse models. a Daily weights of untreated Smn−/−;SMN2 SMA mice and Smn−/−;SMN2 mice that received daily subcutaneous injections (starting at P0) of Fc-TWEAK or IgG control (15.8 μg). Data are mean ± SEM, n = 7–10 animals per experimental group, two-way ANOVA, Sidak’s multiple comparison test. b Survival curves of untreated Smn−/−;SMN2 SMA mice and Smn−/−;SMN2 that received daily subcutaneous injections of Fc-TWEAK or IgG control (15.8 μg). Data are represented as Kaplan-Meier survival curves, n = 7–10 animals per experimental group, log-rank (Mantel-Cox). c–i. qPCR analysis of Tweak (c), Fn14 (d), Pgc-1α (e), Mef2d (f), Glut-4 (g), HKII (h), and Klf15 (i) in triceps of postnatal day (P) 7 untreated and Fc-TWEAK-treated (15.8 μg) Smn−/−;SMN2 SMA and Smn+/−;SMN2 health littermates. Normalized relative expressions for Fc-TWEAK-treated Smn+/−;SMN2 mice are compared to untreated Smn+/−;SMN2 mice, and normalized relative expressions for Fc-TWEAK-treated Smn−/−;SMN2 mice are compared to untreated Smn−/−;SMN2 mice. Data are mean ± SEM, n = 3–4 animals per experimental group, two-way ANOVA, uncorrected Fisher’s LSD between genotypes, *p < 0.05, ***p <0.001. j Representative images of laminin-stained cross sections of TA muscles from P7-untreated and Fc-TWEAK-treated (15.8 μg) Smn−/−;SMN2 SMA and Smn+/−;SMN2 health littermates (Scale bars = 100 μm) and quantification of myofiber area. Data are mean ± SEM, n = 3–4 animals per experimental group (> 550 myofibers per experimental group), one-way ANOVA, Tukey’s multiple comparison test, *p < 0.05, ****p < 0.0001. k Relative frequency distribution of myofiber size in TA muscles of P7-untreated and Fc-TWEAK-treated (15.8 μg) Smn−/−;SMN2 SMA and Smn+/−;SMN2 health littermates. l–p qPCR analysis of parvalbumin (l), MuRF-1 (m), atrogin-1 (n), Myod1 (o), and myogenin (p) in triceps of P7-untreated and Fc-TWEAK-treated (15.8 μg) Smn−/−;SMN2 SMA and Smn+/−;SMN2 health littermates. Normalized relative expressions for Fc-TWEAK-treated Smn+/−;SMN2 mice are compared to untreated Smn+/−;SMN2 mice, and normalized relative expressions for Fc-TWEAK-treated Smn−/−;SMN2 mice are compared to untreated Smn−/−;SMN2 mice. Data are mean ± SEM, n = 3–4 animals per experimental group, two-way ANOVA, uncorrected Fisher’s LSD between genotypes, *p < 0.05, **p <0.01. q Daily weights of untreated Smn2B/− SMA mice and Smn2B/− mice that received subcutaneous injections of Fc-TWEAK or IgG control (15.8 μg) every 4 days (starting at P0). Data are mean ± SEM, n = 9–12 animals per experimental group, two-way ANOVA, Sidak’s multiple comparison test. r Survival curves of untreated Smn2B/− SMA mice and Smn2B/− mice that received subcutaneous injections of Fc-TWEAK or IgG control (15.8 μg) every 4 days (starting at P0). Data are Kaplan-Meier survival curves, n = 9–12 animals per experimental group, log-rank (Mantel-Cox), p = 0.0162. s–x. qPCR analysis of Glut-4 (s), parvalbumin (t), MuRF-1 (u), atrogin-1 (v), Myod1 (w), and myogenin (x) in P15 untreated and Fc-TWEAK-treated (15.8 μg) Smn2B/+ and Smn2B/− mice (every 4 days starting at P0). Normalized relative expressions for Fc-TWEAK-treated Smn2B/+ mice are compared to untreated Smn2B/+ mice, and normalized relative expressions for Fc-TWEAK-treated Smn2B/− mice are compared to untreated Smn2B/− mice. Data are mean ± SEM, n = 3–4 animals per experimental group, two-way ANOVA, uncorrected Fisher’s LSD between genotypes, *p < 0.05, ***p < 0.001, ns, not significant. y Representative images of laminin-stained cross sections of TA muscles from P16 untreated and Fc-TWEAK-treated (15.8 μg every 4 days starting at P0) Smn2B/+ and Smn2B/−mice (scale bars = 50 μm) and quantification of myofiber area. Data are mean ± SEM, n = 3–7 animals per experimental group (> 400 myofibers per experimental group), one-way ANOVA, Tukey’s multiple comparison test, *p < 0.05, ****p < 0.0001. z Relative frequency distribution of myofiber size in TA muscles of P16 untreated and Fc-TWEAK-treated (15.8 μg every 4 days starting at P0) Smn2B/+ and Smn2B/− mice