Novel roles of Atrogin‐1 in cardiac disease, lipid metabolism and bone microstructure

Abstract

Ubiquitination plays a critical role in controlling protein turnover via proteasomal degradation, altering subcellular localization, and regulating protein activity. Functional role(s) for the Atrogin‐1 (MAFbx) ubiquitin ligase in regulating transcription factors have been found in skeletal muscle and the heart, but not in other organs. Within the myocyte, Atrogin‐1 localizes to the sarcomere and nucleus. We have previously reported that Atrogin‐1 is a critical regulator of pathologic and physiologic cardiac hypertrophy in vivo, involving specific interaction and ubiquitination of transcription factors central the signaling pathways driving these hypertrophic responses, including FOXO1/3. Recent studies have linked cardiomyocyte Atrogin‐1 to the regulation of the extracellular matrix. With evidence that cardiomyocyte Atrogin‐1 can affect cells other than myocytes, we analyzed Atrogin‐1−/− mice for their effects on metabolism and bone. DEXA whole body analysis of Atrogin‐1−/− mice revealed significantly decreased fat mass (15.6% vs. 35.8% fat, p<0.05) with a corresponding increase in lean mass (84.4% vs. 64.2%, p<0.05) at the age of 11–15 months, but not at 5 months, when compared to strain‐ and age‐matched wildtype (WT) control mice. Since the Atrogin‐1−/− mice weighed significantly less than WT mice (29±3 vs. 40±2 g, p<0.05), the net fat loss was 4.6 g (vs. 14.3 g in age‐matched WT) and the lean body mass identical between groups (25.7 vs. 24.6 g). Together these findings suggest Atrogin‐1’s role in regulating fat metabolism. Analysis of bone microarchitecture and mechanical properties of adult Atrogin‐1−/− mice was undertaken at 17–21 weeks of age, a time point where no phenotype has been previously observed in skeletal muscle or heart. Femurs were dissected and subsequently assessed by μCT (SkyScan 1172) for bone microarchitecture in the distal femur metaphysis (1 mm) and mid‐diaphysis region and challenged by a three‐point bending test to assess their material and structural properties. No differences in cortical or trabecular bone microarchitecture were identified and nor were any changes in mechanical properties. Together, these findings illustrate novel biological roles of Atrogin‐1 in regulating systemic fat metabolism, possibly involving crosstalk between skeletal muscle/heart and systemic fat metabolism. Our analysis provides an essential framework for the potential therapeutic targeting of ubiquitin ligases like Atrogin‐1 in the context of striated muscle and metabolic disease.Support or Funding InformationSupport: Lilly Foundation/Indiana Center for Musculoskeletal Health/ IU School of Medicine, Physician Scientist Initiative, Scientific Research Initiative