1929-P: Role of miR379 in Promoting Skeletal Muscle Atrophy in Type 1 Diabetes (T1D)

Abstract

T1D can lead to skeletal muscle atrophy which decreases quality of life and increases mortality. Non-coding RNAs such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are increasingly implicated in various pathological conditions. Recently, our lab demonstrated a unique megacluster of ∼ 40 miRNAs including miR379 and their host transcript lnc-MGC (a lncRNA) could induce early features of diabetic kidney disease. Based on new data showing that the expression of miR379 is increased in the atrophied skeletal muscle of T1D mice, in the current study, we investigated the in vivo role of miR379 in promoting skeletal muscle atrophy in vivo in T1D. We used miR379 knockout (KO) mice generated by CRISPR-Cas9 technology. C57BL/6 (WT) and miR379 KO male mice were injected with streptozotocin (STZ 50mg/kg) for 5 consecutive days to induce T1D. miR379 target genes and muscle atrophy markers in the skeletal muscle were analyzed using qPCR. Body composition analysis was performed using Echo-MRI. Fasting blood glucose levels one week after diabetes development, were significantly lower in in miR379 KO mice compared to WT-mice. Moreover, miR379 KO mice showed significant protection from T1D-associated loss in body weight, muscle and fat mass relative to WT mice. Toward interrogating the underlying mechanism, the expression of atrophy-associated genes and miR379 target genes were assessed in skeletal muscle samples. In WT mice, T1D increased the expression of muscle atrophy-associated genes (myostatin and Atrogin1), and decreased FIS1 and EDEM3, miR379 target proteins involved in regulation of mitochondrial health and ER stress respectively. Intriguingly, miR379 KO mice depicted significant protection from these T1D-induced changes. These results suggest miR-379 promotes skeletal muscle atrophy in T1D via upregulating genes involved in muscle wasting and downregulating genes involved in mitochondrial health, thus uncovering novel non-coding RNA dependent mechanisms of skeletal muscle dysfunction in T1D. Disclosure R. Tunduguru: None. M. Kato: None. M. Abdollahi: None. L.L. Lanting: None. R. Natarajan: None. Funding National Institutes of Health