Inhibition of Atrogin-1/MAFbx Expression by Adenovirus-Delivered Small Hairpin RNAs Attenuates Muscle Atrophy in Fasting Mice

Atrogin-1 or muscle atrophy F-box (MAFbx) is a major atrophy-related E3 ubiquitin ligase highly expressed in skeletal muscle during muscle atrophy and other disease states such as sepsis, cancer cachexia, and fasting. In this paper, we report experiments inhibiting MAFbx activity in fasting mice and in the skeletal myoblast cell line C2C12 via an adenovirus-mediated small hairpin RNA (shRNA) expression system in order to assess its suitability as a therapeutic target. Our results demonstrated that downregulation of MAFbx by shRNAs attenuated muscle loss induced by fasting in mice. Furthermore, we showed that when MAFbx expression was blocked both in cells and in fasting mice, the level of a myogenic factor, MyoD, was upregulated; whereas a muscle negative regulator, growth differentiation factor (GDF)-8 (myostatin), was suppressed. Our results also suggested that lower levels of MAFbx could also enhance muscle cell differentiation that corresponded to the reduced expression of GDF-8 and the increased level of MyoD. Taken together, the present study showed that MAFbx could be a potential molecular target for treating muscle atrophy.