Our major hypothesis is that type 2 diabetes mellitus (DM2) induced alterations in skeletal muscle (SkM) mitochondria limit tissue growth and thus, facilitate muscle dysfunction. Specifically, this project will characterize DM2 induced perturbations in SkM mitochondria and their relationship with changes in mediators of muscle growth and differentiation. We intend to demonstrate that the preservation and/or enhancement of mitochondria structure/function will improve SkM growth and consequently, exercise capacity. Currently supported by a 1 year NIDDK seed R24 proposal (""""""""Targeting cellular bioenergetics for the prevention and treatment of diabetes"""""""") this research team has characterized the positive effects of the primary flavanol present in cacao, (-)-epicatechin (Epi) on mitochondria related endpoints. Thus, the use of this class of compounds can serve as a powerful tool to pursue our major objective and generate evidence for their therapeutic potential. Our studies in mice and primary human cells demonstrate that Epi, stimulates SkM mitochondrial mass/volume and increases maximal mitochondrial respiratory rate. Further, mice treated with 1 mg/kg BID Epi by gavage for 15 days demonstrate enhanced SkM function, endurance, mitochondrial volume, cristae density and capillarity. We recently published the results of a study performed in heart failure DM2 patients in which Epi rich cocoa administration restored SkM (quadriceps) mitochondrial cristae density and increased protein and activity levels of multiple indicators of mitochondria biogenesis. We have also documented at baseline, severe perturbations in SkM structure and sarcomere organization. Interestingly, perturbations in mitochondrial biogenesis are linked to disruptions in muscle regeneration and differentiation. Indeed, following treatment with Epi rich cocoa sarcomere organization was improved as well as markers of muscle growth/regeneration including myostatin, follistatin and MyoD amongst others. Through our collaborative efforts, we have also synthetized more potent Epi isomer forms and novel derivatives active in the low nM range. These results pave the way for the future use of Epi (and patentable related compounds) as therapeutic agents for the treatment DM2 induced SkM related pathologies which are also likely to improve disease profile. To reveal the mechanisms responsible for these responses, we will test the following hypotheses:
Aim 1. Hypothesis: The presence of DM2 leads to perturbations in SkM mitochondria structure/function, which adversely impacts regulators of growth and differentiation.
Aim 2. Hypothesis: The in vitro stimulation of mitochondria structure/function restores DM2 induced loss of SkM differentiation and growth potential.
Aim 3. Hypothesis: The in vivo stimulation of mitochondria structure/function reverses DM2 induced loss of SkM growth and function. This translational proposal is to further the R24 supported ongoing collaboration of Epi biology, diabetology and muscle physiology experts to provide rigorous pre-clinical results to be used for the planning and implementation of relevant clinical trials in DM2 patients.

Public Health Relevance

The major goal of this proposal is to determine the role that mitochondria play in allowing for muscle growth to occur in the setting of type 2 diabetes. We propose to test this hypothesis by using a class of novel and effective compounds that stimulate mitochondria formation and thus, likely muscle growth. Thus, the science advanced by this proposal may allow us to develop safe and effective new therapies to treat diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Pawlyk, Aaron
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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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
Moreno-Ulloa, Aldo; Nájera-García, Nayelli; Hernández, Marcela et al. (2018) A pilot study on clinical pharmacokinetics and preclinical pharmacodynamics of (+)-epicatechin on cardiometabolic endpoints. Food Funct 9:307-319
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
Varela, Claudia Elena; Fromentin, Emilie; Roller, Marc et al. (2016) Effects of a natural extract of Aronia Melanocarpa berry on endothelial cell nitric oxide production. J Food Biochem 40:404-410
Ramírez-Sánchez, Israel; Rodríguez, Alonso; Moreno-Ulloa, Aldo et al. (2016) (-)-Epicatechin-induced recovery of mitochondria from simulated diabetes: Potential role of endothelial nitric oxide synthase. Diab Vasc Dis Res 13:201-10
Ciaraldi, Theodore P; Ryan, Alexander J; Mudaliar, Sunder R et al. (2016) Altered Myokine Secretion Is an Intrinsic Property of Skeletal Muscle in Type 2 Diabetes. PLoS One 11:e0158209
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Moreno-Ulloa, Aldo; Mendez-Luna, David; Beltran-Partida, Ernesto et al. (2015) The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER). Pharmacol Res 100:309-20
Gutiérrez-Salmeán, Gabriela; Ortiz-Vilchis, Pilar; Vacaseydel, Claudia M et al. (2014) Acute effects of an oral supplement of (-)-epicatechin on postprandial fat and carbohydrate metabolism in normal and overweight subjects. Food Funct 5:521-7
Gutiérrez-Salmeán, Gabriel; Ortiz-Vilchis, Pilar; Vacaseydel, Claudia Maria et al. (2014) Effects of (-)-epicatechin on a diet-induced rat model of cardiometabolic risk factors. Eur J Pharmacol 728:24-30

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