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Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity.

ABSTRACT: Aging is characterized by a progressive loss of skeletal muscle mass and function (sarcopenia). Obesity exacerbates age-related decline and lead to frailty. Skeletal muscle fat infiltration increases with aging and seems to be crucial for the progression of sarcopenia. Additionally, skeletal muscle plasticity modulates metabolic adaptation to different pathophysiological situations. Thus, cellular bioenergetics and mitochondrial profile were studied in the skeletal muscle of overweight aged people without reaching obesity to prevent this extreme situation. Overweight aged muscle lacked ATP production, as indicated by defects in the phosphagen system, glycolysis and especially mostly by oxidative phosphorylation metabolic pathway. Overweight subjects exhibited an inhibition of mitophagy that was linked to an increase in mitochondrial biogenesis that underlies the accumulation of dysfunctional mitochondria and encourages the onset of sarcopenia. As a strategy to maintain cellular homeostasis, overweight subjects experienced a metabolic switch from oxidative to lactic acid fermentation metabolism, which allows continued ATP production under mitochondrial dysfunction, but without reaching physiological aged basal levels. This ATP depletion induced early signs of impaired contractile function and a decline in skeletal muscle structural integrity, evidenced by lower levels of filamin C. Our findings reveal the main effector pathways at an early stage of obesity and highlight the importance of mitochondrial metabolism in overweight and obese individuals. Exploiting mitochondrial profiles for therapeutic purposes in humans is an ambitious strategy for treating muscle impairment diseases.

SUBMITTER: Potes Y

PROVIDER: S-EPMC6457058 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity.

Potes Yaiza Y Pérez-Martinez Zulema Z Bermejo-Millo Juan C JC Rubio-Gonzalez Adrian A Fernandez-Fernández María M Bermudez Manuel M Arche Jose M JM Solano Juan J JJ Boga Jose A JA Oliván Mamen M Caballero Beatriz B Vega-Naredo Ignacio I Coto-Montes Ana A

Aging and disease 20190401 2

Aging is characterized by a progressive loss of skeletal muscle mass and function (sarcopenia). Obesity exacerbates age-related decline and lead to frailty. Skeletal muscle fat infiltration increases with aging and seems to be crucial for the progression of sarcopenia. Additionally, skeletal muscle plasticity modulates metabolic adaptation to different pathophysiological situations. Thus, cellular bioenergetics and mitochondrial profile were studied in the skeletal muscle of overweight aged peop ...[more]

PMID: 31011474

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Project description:BackgruoundPrevious studies have reported that oxidative stress contributes to obesity characterized by adipocyte hypertrophy. However, mechanism has not been studied extensively. In the current study, we evaluated role of extracellular vimentin secreted by oxidized low-density lipoprotein (oxLDL) in energy metabolism in adipocytes.MethodsWe treated 3T3-L1-derived adipocytes with oxLDL and measured vimentin which was secreted in the media. We evaluated changes in uptake of glucose and free fatty acid, expression of molecules functioning in energy metabolism, synthesis of adenosine triphosphate (ATP) and lactate, markers for endoplasmic reticulum (ER) stress and autophagy in adipocytes treated with recombinant vimentin.ResultsAdipocytes secreted vimentin in response to oxLDL. Microscopic evaluation revealed that vimentin treatment induced increase in adipocyte size and increase in sizes of intracellular lipid droplets with increased intracellular triglyceride. Adipocytes treated with vimentin showed increased uptake of glucose and free fatty acid with increased expression of plasma membrane glucose transporter type 1 (GLUT1), GLUT4, and CD36. Vimentin treatment increased transcription of GLUT1 and hypoxia-inducible factor 1α (Hif-1α) but decreased GLUT4 transcription. Adipose triglyceride lipase (ATGL), peroxisome proliferator-activated receptor γ (PPARγ), sterol regulatory element-binding protein 1 (SREBP1), diacylglycerol O-acyltransferase 1 (DGAT1) and 2 were decreased by vimentin treatment. Markers for ER stress were increased and autophagy was impaired in vimentin-treated adipocytes. No change was observed in synthesis of ATP and lactate in the adipocytes treated with vimentin.ConclusionWe concluded that extracellular vimentin regulates expression of molecules in energy metabolism and promotes adipocyte hypertrophy. Our results show that vimentin functions in the interplay between oxidative stress and metabolism, suggesting a mechanism by which adipocyte hypertrophy is induced in oxidative stress.

Dataset Information

Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity.

Publications

Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity.

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