Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals
Reduced mitochondrial capacity in skeletal muscle has been observed in obesity and type 2 diabetes. In humans, the aetiology of this abnormality is not well understood but the possibility that it is secondary to the stress of nutrient overload has been suggested. To test this hypothesis, we examined whether sustained overfeeding decreases skeletal muscle mitochondrial content or impairs function.
Twenty-six healthy volunteers (21 men, 5 women, age 25.3 ± 4.5 years, BMI 25.5 ± 2.4 kg/m2) underwent a supervised protocol consisting of 8 weeks of high-fat overfeeding (40% over baseline energy requirements). Before and after overfeeding, we measured systemic fuel oxidation by indirect calorimetry and performed skeletal muscle biopsies to measure mitochondrial gene expression, content and function in vitro. Mitochondrial function in vivo was measured by 31P NMR spectroscopy.
With overfeeding, volunteers gained 7.7 ± 1.8 kg (% change 9.8 ± 2.3). Overfeeding increased fasting NEFA, LDL-cholesterol and insulin concentrations. Indirect calorimetry showed a shift towards greater reliance on lipid oxidation. In skeletal muscle tissue, overfeeding increased ceramide content, lipid droplet content and perilipin-2 mRNA expression. Phosphorylation of AMP-activated protein kinase was decreased. Overfeeding increased mRNA expression of certain genes coding for mitochondrial proteins (CS, OGDH, CPT1B, UCP3, ANT1). Despite the stress of nutrient overload, mitochondrial content and mitochondrial respiration in muscle did not change after overfeeding. Similarly, overfeeding had no effect on either the emission of reactive oxygen species or on mitochondrial function in vivo.
Skeletal muscle mitochondria are significantly resilient to nutrient overload. The lower skeletal muscle mitochondrial oxidative capacity in human obesity is likely to be caused by reasons other than nutrient overload per se.
KeywordsHuman Insulin resistance Insulin sensitivity Mitochondria Obesity
AMP-activated protein kinase
Physical activity level
Peroxisome proliferator-activated receptor-γ coactivator-1α
Reactive oxygen species
Sleep metabolic rate
Total daily energy expenditure
We thank D. Stoltz (Center for Biological Imaging, University of Pittsburgh, PA, USA) for assistance with electron microscopy and E. Leachman (Dept of Medicine, University of Pittsburgh, PA, USA) and P. Coen (Translational Research Institute for Metabolism and Diabetes, USA) for assistance with succinate dehydrogenase histology.
All data generated or analysed during this study are included in this published article.
This work was supported by NIH grants R01DK060412 and K01DK89005 and by NORC Center Grant P30DK72476.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
FGST and ER designed the study, analysed the data and wrote the manuscript. FGST was responsible for the study concept. All authors participated in data acquisition, revised the manuscript critically for intellectual content and approved the final version. ER is the guarantor of this work.
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