Many disease processes involve activation of a “fetal gene program”. H19X-encodes a number of non-coding RNAs including miR-424, miR-503, miR503HG, miR-542, miR-450a1, miR-450a2 and miR-450b that are specifically expressed in embryonic heart and muscles. They are not normally express in adult tissues, but they are activated in muscle wasting associated with cancer and chronic diseases, in sarcopenia (age-related muscle wasting), and in heart failure. Using mouse models, we demonstrated that activation of H19X genes caused skeletal muscle wasting and heart failure; whereas knockout of H19X genes preserves muscle in starvation-induced muscle wasting. We further demonstrated that antisense-based inhibitors of miR-424/miR-503 preserves muscle in wasting conditions. We claim that antagomirs, RNA-sponge, and Crispr-mediated promoter silencing targeting H19X non-coding RNAs are effective treatment of muscle wasting, cachexia, sarcopenia and heart failure.