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

doi:10.1007/s00125-020-05128-1

Lena Bilet, Matthijs K C Hesselink + Show 14 more

Open Access

https://doi.org/10.1007/s00125-020-05128-1

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Abstract

Aims/hypothesisPhysical 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.MethodsHere 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/m2) underwent a 12 day unilateral lower-limb suspension with the contralateral leg serving as an active internal control.ResultsIn vivo, mitochondrial oxidative capacity, assessed by phosphocreatine (PCr)-recovery half-time, was lower in the inactive vs active leg. Ex vivo, palmitate oxidation to 14CO2 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/interpretationTogether, 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 registrationClinicalTrial.gov NCT01576250.FundingPS was supported by a ‘VICI’ Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 918.96.618).

Highlights

Physical inactivity is a major determinant of the current epidemic of chronic metabolic disorders, like obesity and type 2 diabetes mellitus [1, 2]
These findings suggest that the imbalance between skeletal muscle fat accumulation and a low mitochondrial oxidative capacity determines the development of insulin resistance
Physical inactivity-associated low skeletal muscle mitochondrial oxidative capacity is suggested to contribute to skeletal muscle fat accumulation and insulin resistance [19, 20] and thereby is thought to be involved in the development of type 2 diabetes

Summary

Introduction

Physical inactivity is a major determinant of the current epidemic of chronic metabolic disorders, like obesity and type 2 diabetes mellitus [1, 2]. In contrast to the well-known high mitochondrial capacity of endurance-trained athletes, several (but not all [17, 18]) studies have found that insulinresistant individuals with type 2 diabetes are characterised by impaired mitochondrial oxidative capacity [19,20,21,22]. These findings suggest that the imbalance between skeletal muscle fat accumulation and a low mitochondrial oxidative capacity determines the development of insulin resistance

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