The major objective of this exploratory/developmental R21 proposal is to gather preliminary data to validate the future testing of (-)-epicatechin (Epi) for the treatment of sarcopenia. One of the most notable and debilitating age-associated alterations is the progressive loss of fat-free skeletal muscle (SkM) mass and strength, a condition known as sarcopenia. Currently, only exercise is recognized as an effective intervention to counteract sarcopenia. Thus, the need to identify and validate safe and novel pharmacological strategies to effectively treat loss of muscle mass and strength. Our recent studies in animals demonstrate that (-)-epicatechin (Epi), the primary flavanol present in cacao, enhances SkM structure/function to levels comparable to those triggered by exercise. Preliminary studies performed in young and senescent mice indicate that Epi treatment can significantly decrease SkM protein levels of myostatin while increasing those of follistatin and multiple indicators of oxidative capacity suggesting possible stimulatory effects on muscle mass. In a proof-of-concept study, five healthy subjects were provided Epi in capsules for 7 days and blood protein levels of myostatin and follistatin measured. Results indicate a significant increase in the ratio of follistatin/myostatin. We also performed pharmacokinetic studies of Epi in human subjects noting a lack of adverse effects confirming, published reports regarding its wide safety margin. Given these novel observations, it is reasonable to propose an exploratory clinical trial to serve as an initial foundation for future sarcopenia-related studies. We specifically hypothesize that Epi can increase SkM mass and/or oxidative capacity leading to enhanced muscle function. These effects will be evidenced in older subjects and be linked to reductions in muscle and blood levels of myostatin, increases in follistatin, markers of muscle differentiation and indicators of oxidative capacity. We will pursue the following aims:
Aim 1. To examine the effects of Epi treatment in older subjects (age 65-75) on SkM mass and function. Using a randomized, double blinded clinical trial; we will examine the effects of a 6 month treatment with Epi (versus placebo) on muscle mass and function.
Aim 2. To examine the effects of Epi treatment in healthy older subjects on SkM blood and muscle levels of myostatin and follistatin, SkM oxidative capacity and regulators of differentiation. Biopsies of quadriceps muscle (Vastus Lateralis) will be collected at the beginning and at the end of the 6 month trial. Blood samples will be collected serially (every month) during the study. Using Western blots, we will compare muscle protein levels for the endpoints of interest. We will also determine myofiber cross-sectional area and fat infiltration. In blood samples, we will assay circulating levels of Epi (and related metabolites). Using ELISA kits we will measure blood levels of myostatin and follistatin and determine the time course of changes during treatment.
The loss of muscle mass and strength is a major cause of disability and increases the likelihood of death in older, frail subjects. Currently, only exercise has demonstrated a benefit in treating muscle weakness. This novel, exploratory study aims to evaluate the capacity of epicatechin (a natural supplement derived from cocoa) treatment to improve muscle mass and function in older subjects.
|Moreno-Ulloa, Aldo; Miranda-Cervantes, Adriana; Licea-Navarro, Alexei et al. (2018) (-)-Epicatechin stimulates mitochondrial biogenesis and cell growth in C2C12 myotubes via the G-protein coupled estrogen receptor. Eur J Pharmacol 822:95-107|
|Sarmiento, Viviana; Ramirez-Sanchez, Israel; Moreno-Ulloa, Aldo et al. (2018) Synthesis of novel (-)-epicatechin derivatives as potential endothelial GPER agonists: Evaluation of biological effects. Bioorg Med Chem Lett 28:658-663|