Inhibition of ERK pathway by AZD6244 (Selumetinib) significantly enhances SMN expression and AKT activation, increases lifespan, and improves weight curve in severe SMA-like mice. A, B, Western blot analysis and quantification of SMN protein expression in the ventral lumbar spinal cord of vehicle- and AZD6244-treated control mice at 2 and 6 d of age, vehicle-treated SMA-like mice at 2 d of age, and AZD6244-treated SMA-like mice at 2 and 6 d of age (n = 3). C, D, Western blot analysis and quantification of SMN protein expression in brain, heart, kidneys, lungs, liver, diaphragm, and tibialis of AZD6244-treated SMA-like mice at 2 d of age (n = 3). E, F, Western blot analysis and quantification of AKT protein phosphorylation in the ventral lumbar spinal cord of vehicle- and AZD6244-treated control mice at 2 and 6 d of age, vehicle-treated SMA-like mice at 2 d of age, and AZD6244-treated SMA-like mice at 2 and 6 d of age (n = 3). G, Lifespan of AZD6244-treated SMA-like mice (n = 11) compared with vehicle-treated (n = 13) and untreated (n = 10) SMA-like mice. H, Weight curve in AZD6244-treated (n = 11) and vehicle-treated SMA-like (n = 13) mice compared with AZD6244-treated (n = 10) and vehicle-treated control (n = 10) mice. Data are displayed as mean ± SEM. *p < 0.05, ***p < 0.001.