One-leg inactivity induces a reduction in mitochondrial oxidative capacity, intramyocellular lipid accumulation and reduced insulin signalling upon lipid infusion: a human study with unilateral limb suspension

Lena Bilet, Esther Phielix, Tineke van de Weijer, Anne Gemmink, Madeleen Bosma, Esther Moonen-Kornips, Johanna A. Jorgensen, Gert Schaart, Dongyan Zhang, Kenneth Meijer, Maria Hopman, Matthijs K. C. Hesselink, D. Margriet Ouwens, Gerald I. Shulman, Vera B. Schrauwen-Hinderling, Patrick Schrauwen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims/hypothesis: Physical inactivity, low mitochondrial function, increased intramyocellular lipid (IMCL) deposition and reduced insulin sensitivity are common denominators of chronic metabolic disorders, like obesity and type 2 diabetes. Yet, whether low mitochondrial function predisposes to insulin resistance in humans is still unknown. Methods: Here we investigated, in an intervention study, whether muscle with low mitochondrial oxidative capacity, induced by one-legged physical inactivity, would feature stronger signs of lipid-induced insulin resistance. To this end, ten male participants (age 22.4 ± 4.2 years, BMI 21.3 ± 2.0 kg/m 2) underwent a 12 day unilateral lower-limb suspension with the contralateral leg serving as an active internal control. Results: In vivo, mitochondrial oxidative capacity, assessed by phosphocreatine (PCr)-recovery half-time, was lower in the inactive vs active leg. Ex vivo, palmitate oxidation to 14CO 2 was lower in the suspended leg vs the active leg; however, this did not result in significantly higher [ 14C]palmitate incorporation into triacylglycerol. The reduced mitochondrial function in the suspended leg was, however, paralleled by augmented IMCL content in both musculus tibialis anterior and musculus vastus lateralis, and by increased membrane bound protein kinase C (PKC) θ. Finally, upon lipid infusion, insulin signalling was lower in the suspended vs active leg. Conclusions/interpretation: Together, these results demonstrate, in a unique human in vivo model, that a low mitochondrial oxidative capacity due to physical inactivity directly impacts IMCL accumulation and PKCθ translocation, resulting in impaired insulin signalling upon lipid infusion. This demonstrates the importance of mitochondrial oxidative capacity and muscle fat accumulation in the development of insulin resistance in humans. Trial registration: ClinicalTrial.gov NCT01576250. Funding: PS was supported by a ‘VICI’ Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 918.96.618).

Original languageEnglish
Pages (from-to)1211-1222
Number of pages12
JournalDiabetologia
Volume63
Issue number6
DOIs
Publication statusPublished - Jun 2020

Keywords

  • Fat oxidation
  • Insulin resistance
  • Intramyocellular lipid content
  • Mitochondrial function
  • Mitochondrial oxidative capacity
  • Physical inactivity
  • Unilateral lower-limb suspension
  • SKELETAL-MUSCLE
  • PHYSICAL INACTIVITY
  • SKIN TEMPERATURE
  • FATTY-ACIDS
  • ECTOPIC FAT
  • PKC-THETA
  • RESISTANCE
  • DYSFUNCTION
  • EXERCISE
  • AGE

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