Resveratrol ameliorates muscle atrophy in chronic kidney disease via the axis of SIRT1/FoxO1.

Chronic kidney disease (CKD) is often associated with muscle atrophy. However, the underlying molecular mechanisms are still not well understood. Here, we treated 5/6-nephrectomized (5/6Nx) rats with resveratrol and found that this treatment greatly improves renal function as evidenced by reduced proteinuria and cystatin C. Moreover, resveratrol ameliorates renal fibrosis by reducing transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF). Meanwhile, muscle atrophy in these 5/6Nx rats was largely attenuated by resveratrol. Immunoprecipitation revealed that SIRT1 physically interacts with FoxO1 in muscle, and this interaction was weakened in 5/6Nx rats. As a consequence, acetylated FoxO1 was increased in muscle of 5/6Nx rats. The application of resveratrol markedly reverses this trend. These data point out that SIRT1 is a key factor for linking renal disease and muscle atrophy. Indeed, both renal dysfunction and muscle atrophy were further aggravated by 5/6Nx in Sirt1+/- mice. Taken together, our data indicate that SIRT1 plays a pivotal role in muscle atrophy in CKD, and FoxO1 might be a substrate of SIRT1 in this process. Furthermore, resveratrol, together with other agonists of SIRT1, may hold great therapeutic potentials for treating CKD and its related muscle atrophy.