Myocardin reverses insulin resistance and ameliorates cardiomyopathy by increasing IRS-1 expression in a murine model of lipodystrophy caused by adipose deficiency of vacuolar H+-ATPase V0d1 subunit.

Aim: Adipose tissue (AT) dysfunction that occurs in both obesity and lipodystrophy is associated with the development of cardiomyopathy. However, it is unclear how dysfunctional AT induces cardiomyopathy due to limited animal models available. We have identified vacuolar H+-ATPase subunit Vod1, encoded by Atp6v0d1, as a master regulator of adipogenesis, and adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO) in mice caused generalized lipodystrophy and spontaneous cardiomyopathy. Using this unique animal model, we explore the mechanism(s) underlying lipodystrophy-related cardiomyopathy. Methods and Results: Atp6v0d1AKO mice developed cardiac hypertrophy at 12 weeks, and progressed to heart failure at 28 weeks. The Atp6v0d1AKO mouse hearts exhibited excessive lipid accumulation and altered lipid and glucose metabolism, which are typical for obesity- and diabetes-related cardiomyopathy. The Atp6v0d1AKO mice developed cardiac insulin resistance evidenced by decreased IRS-1/2 expression in hearts. Meanwhile, the expression of forkhead box O1 (FoxO1), a transcription factor which plays critical roles in regulating cardiac lipid and glucose metabolism, was increased. RNA-seq data and molecular biological assays demonstrated reduced expression of myocardin, a transcription coactivator, in Atp6v0d1AKO mouse hearts. RNA interference (RNAi), luciferase reporter and ChIP-qPCR assays revealed the critical role of myocardin in regulating IRS-1 transcription through the CArG-like element in IRS-1 promoter. Reducing IRS-1 expression with RNAi increased FoxO1 expression, while increasing IRS-1 expression reversed myocardin downregulation-induced FoxO1 upregulation in cardiomyocytes. In vivo, restoring myocardin expression specifically in Atp6v0d1AKO cardiomyocytes increased IRS-1, but decreased FoxO1 expression. As a result, the abnormal expressions of metabolic genes in Atp6v0d1AKO hearts were reversed, and cardiac dysfunctions were ameliorated. Myocardin expression was also reduced in high fat diet-induced diabetic cardiomyopathy and palmitic acid-treated cardiomyocytes. Moreover, increasing systemic insulin resistance with rosiglitazone restored cardiac myocardin expression and improved cardiac functions in Atp6v0d1AKO mice. Conclusion: Atp6v0d1AKO mice are a novel animal model for studying lipodystrophy- or metabolic dysfunction-related cardiomyopathy. Moreover, myocardin serves as a key regulator of cardiac insulin sensitivity and metabolic homeostasis, highlighting myocardin as a potential therapeutic target for treating lipodystrophy- and diabetes-related cardiomyopathy.

Agricultural management strategies for balancing yield increase, carbon sequestration, and emission reduction after straw return for three major grain crops in China: A meta-analysis.

Straw return can improve crop yield as well as soil organic carbon (SOC) but may raise the possibility of N2O and CH4 emissions. However, few studies have compared the effects of straw return on the yield, SOC, and N2O emissions of various crops. Which management strategies are the best for balancing yield, SOC, and emission reduction for various crops needs to be clarified. A meta-analysis containing 2269 datasets collected from 369 studies was conducted to investigate the influence of agricultural management strategies on yield increase, soil carbon sequestration, and emission reduction in various crops after the straw return. Analytical results indicated that, on average, straw return increased the yield of rice, wheat, and maize by 5.04%, 8.09%, and 8.71%, respectively. Straw return increased maize N2O emissions by 14.69% but did not significantly affect wheat N2O emissions. Interestingly, straw return reduced the rice N2O emissions by 11.43% but increased the CH4 emissions by 72.01%. The recommended nitrogen application amounts for balancing yield, SOC, and emission reduction varied among the three crops, while the recommended straw return amounts were more than 9000 kg/ha. The optimal tillage and straw return strategies for rice, wheat, and maize were plow tillage combined with incorporation, rotary tillage combined with incorporation, and no-tillage combined with mulching, respectively. A straw return duration of 5-10 years for rice and maize and ≤5 years for wheat was recommended. These findings provide optimal agricultural management strategies after straw return to balance the crop yield, SOC, and emission reduction for China's three major grain crops.