nach oben

Erschienen in:

17.11.2017 | Article

Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals

verfasst von: Frederico G. S. Toledo, Darcy L. Johannsen, Jeffrey D. Covington, Sudip Bajpeyi, Bret Goodpaster, Kevin E. Conley, Eric Ravussin

Erschienen in: Diabetologia | Ausgabe 2/2018

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypotheses

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

Trial registration

ClinicalTrials.gov NCT01672632.

Kelley D, He J, Menshikova E, Ritov V (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes mellitus. Diabetes 51:2944–2950CrossRefPubMed

Chomentowski P, Coen PM, Radikova Z, Goodpaster BH, Toledo FG (2011) Skeletal muscle mitochondria in insulin resistance: differences in intermyofibrillar versus subsarcolemmal subpopulations and relationship to metabolic flexibility. J Clin Endocrinol Metab 96:494–503CrossRefPubMed

Toledo FG (2014) Mitochondrial involvement in skeletal muscle insulin resistance. Diabetes 63:59–61CrossRefPubMed

Holloszy JO (2013) ʻDeficiencyʼ of mitochondria in muscle does not cause insulin resistance. Diabetes 62:1036–1040CrossRefPubMedPubMedCentral

Kelley DE, Goodpaster B, Wing RR, Simoneau JA (1999) Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Phys 277:E1130–E1141CrossRef

Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671CrossRefPubMedPubMedCentral

Goodpaster BH (2013) Mitochondrial deficiency is associated with insulin resistance. Diabetes 62:1032–1035CrossRefPubMedPubMedCentral

DeLany JP, Dube JJ, Standley RA et al (2014) Racial differences in peripheral insulin sensitivity and mitochondrial capacity in the absence of obesity. J Clin Endocrinol Metab 99:4307–4314CrossRefPubMedPubMedCentral

Richardson DK, Kashyap S, Bajaj M et al (2005) Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 280:10290–10297CrossRefPubMed

10.

Sparks LM, Xie H, Koza RA et al (2005) A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54:1926–1933CrossRefPubMed

11.

Hancock CR, Han DH, Chen M et al (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci U S A 105:7815–7820CrossRefPubMedPubMedCentral

12.

Holloway GP, Gurd BJ, Snook LA, Lally J, Bonen A (2010) Compensatory increases in nuclear PGC1α protein are primarily associated with subsarcolemmal mitochondrial adaptations in ZDF rats. Diabetes 59:819–828CrossRefPubMedPubMedCentral

13.

Turner N, Bruce CR, Beale SM et al (2007) Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56:2085–2092CrossRefPubMed

14.

Johannsen DL, Tchoukalova Y, Tam CS et al (2014) Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the ʻadipose tissue expandabilityʼ hypothesis. Diabetes Care 37:2789–2797CrossRefPubMedPubMedCentral

15.

Heilbronn LK, de Jonge L, Frisard MI et al (2006) Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 295:1539–1548CrossRefPubMedPubMedCentral

16.

Bray GA, Smith SR, de Jonge L et al (2012) Effect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: a randomized controlled trial. JAMA 307:47–55CrossRefPubMedPubMedCentral

17.

Nguyen T, de Jonge L, Smith SR, Bray GA (2003) Chamber for indirect calorimetry with accurate measurement and time discrimination of metabolic plateaus of over 20 min. Med Biol Eng Comput 41:572–578CrossRefPubMed

18.

Johannsen DL, Calabro MA, Stewart J, Franke W, Rood JC, Welk GJ (2010) Accuracy of armband monitors for measuring daily energy expenditure in healthy adults. Med Sci Sports Exerc 42:2134–2140CrossRefPubMed

19.

Bergstrom J (1975) Percutaneous needle biopsy of skeletal muscle in physiological and clinical research. Scand J Clin Lab Invest 35:609–616CrossRefPubMed

20.

Obanda DN, Hernandez A, Ribnicky D et al (2012) Bioactives of Artemisia dracunculus L. mitigate the role of ceramides in attenuating insulin signaling in rat skeletal muscle cells. Diabetes 61:597–605CrossRefPubMedPubMedCentral

21.

Toledo FG, Watkins S, Kelley DE (2006) Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women. J Clin Endocrinol Metab 91:3224–3227CrossRefPubMed

22.

Toledo FG, Menshikova EV, Ritov VB et al (2007) Effects of physical activity and weight loss on skeletal muscle mitochondria and relationship with glucose control in type 2 diabetes. Diabetes 56:2142–2147CrossRefPubMed

23.

Pruchnic R, Katsiaras A, He J, Kelley DE, Winters C, Goodpaster BH (2004) Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Phys Endocrinol Metab 287:E857–E862CrossRef

24.

Bogacka I, Xie H, Bray GA, Smith SR (2005) Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54:1392–1399CrossRefPubMed

25.

Lefort N, Glancy B, Bowen B et al (2010) Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes 59:2444–2452CrossRefPubMedPubMedCentral

26.

Seifert EL, Estey C, Xuan JY, Harper ME (2010) Electron transport chain-dependent and -independent mechanisms of mitochondrial H₂O₂ emission during long-chain fatty acid oxidation. J Biol Chem 285:5748–5758CrossRefPubMed

27.

St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277:44784–44790CrossRefPubMed

28.

Chappell JB, Perry SV (1954) Biochemical and osmotic properties of skeletal muscle mitochondria. Nature 173:1094–1095CrossRefPubMed

29.

Seifert EL, Bezaire V, Estey C, Harper ME (2008) Essential role for uncoupling protein-3 in mitochondrial adaptation to fasting but not in fatty acid oxidation or fatty acid anion export. J Biol Chem 283:25124–25131CrossRefPubMed

30.

Amara CE, Marcinek DJ, Shankland EG, Schenkman KA, Arakaki LS, Conley KE (2008) Mitochondrial function in vivo: spectroscopy provides window on cellular energetics. Methods 46:312–318CrossRefPubMed

31.

Jubrias SA, Esselman PC, Price LB, Cress ME, Conley KE (2001) Large energetic adaptations of elderly muscle to resistance and endurance training. J Appl Physiol 90:1663–1670CrossRefPubMed

32.

Jubrias SA, Crowther GJ, Shankland EG, Gronka RK, Conley KE (2003) Acidosis inhibits oxidative phosphorylation in contracting human skeletal muscle in vivo. J Physiol 553:589–599CrossRefPubMedPubMedCentral

33.

Conley KE, Jubrias SA, Esselman PC (2000) Oxidative capacity and ageing in human muscle. J Physiol 526:203–210CrossRefPubMedPubMedCentral

34.

Blei ML, Conley KE, Kushmerick MJ (1993) Separate measures of ATP utilization and recovery in human skeletal muscle. J Physiol 465:203–222CrossRefPubMedPubMedCentral

35.

Blei ML, Conley KE, Odderson IB, Esselman PC, Kushmerick MJ (1993) Individual variation in contractile cost and recovery in a human skeletal muscle. Proc Natl Acad Sci U S A 90:7396–7400CrossRefPubMedPubMedCentral

36.

Kogot-Levin A, Saada A (2014) Ceramide and the mitochondrial respiratory chain. Biochimie 100:88–94CrossRefPubMed

37.

Yu J, Novgorodov SA, Chudakova D et al (2007) JNK3 signaling pathway activates ceramide synthase leading to mitochondrial dysfunction. J Biol Chem 282:25940–25949CrossRefPubMed

38.

Simoneau JA, Veerkamp JH, Turcotte LP, Kelley DE (1999) Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J 13:2051–2060PubMed

39.

Toledo FG, Menshikova EV, Azuma K et al (2008) Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57:987–994CrossRefPubMed

40.

Coen PM, Menshikova EV, Distefano G et al (2015) Exercise and weight loss improve muscle mitochondrial respiration, lipid partitioning, and insulin sensitivity after gastric bypass surgery. Diabetes 64:3737–3750CrossRefPubMedPubMedCentral

41.

Berggren JR, Boyle KE, Chapman WH, Houmard JA (2008) Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise. Am J Phys Endocrinol Metab 294:E726–E732CrossRef

42.

Samocha-Bonet D, Campbell LV, Mori TA et al (2012) Overfeeding reduces insulin sensitivity and increases oxidative stress, without altering markers of mitochondrial content and function in humans. PLoS One 7:e36320CrossRefPubMedPubMedCentral

43.

Larsen S, Nielsen J, Hansen CN et al (2012) Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol 590:3349–3360CrossRefPubMedPubMedCentral

44.

Dirks ML, Wall BT, van de Valk B et al (2016) One week of bed rest leads to substantial muscle atrophy and induces whole-body insulin resistance in the absence of skeletal muscle lipid accumulation. Diabetes 65:2862–2875CrossRefPubMed

45.

Gram M, Vigelsø A, Yokota T et al (2014) Two weeks of one-leg immobilization decreases skeletal muscle respiratory capacity equally in young and elderly men. Exp Gerontol 58:269–278CrossRefPubMed

Titel: Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals
verfasst von: Frederico G. S. Toledo
Darcy L. Johannsen
Jeffrey D. Covington
Sudip Bajpeyi
Bret Goodpaster
Kevin E. Conley
Eric Ravussin
Publikationsdatum: 17.11.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 2/2018
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-017-4496-8

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Klimawandel und Gesundheit: Was Sie in der Hausarztpraxis wissen müssen und tun können

Springer Medizin

Impact of prolonged overfeeding on skeletal muscle mitochondria in healthy individuals