The effect of age and unilateral leg immobilization for 2 weeks on substrate utilization during moderate‐intensity exercise in human skeletal muscle
Open accessAbstract
Key points: This study aimed to provide molecular insight into the differential effects of age and physical inactivity on the regulation of substrate metabolism during moderate‐intensity exercise. Using the arteriovenous balance technique, we studied the effect of immobilization of one leg for 2 weeks on leg substrate utilization in young and older men during two‐legged dynamic knee‐extensor moderate‐intensity exercise, as well as changes in key proteins in muscle metabolism before and after exercise. Age and immobilization did not affect relative carbohydrate and fat utilization during exercise, but the older men had higher uptake of exogenous fatty acids, whereas the young men relied more on endogenous fatty acids during exercise. Using a combined whole‐leg and molecular approach, we provide evidence that both age and physical inactivity result in intramuscular lipid accumulation, but this occurs only in part through the same mechanisms. Age and inactivity have been associated with intramuscular triglyceride (IMTG) accumulation. Here, we attempt to disentangle these factors by studying the effect of 2 weeks of unilateral leg immobilization on substrate utilization across the legs during moderate‐intensity exercise in young (n = 17; 23 ± 1 years old) and older men (n = 15; 68 ± 1 years old), while the contralateral leg served as the control. After immobilization, the participants performed two‐legged isolated knee‐extensor exercise at 20 ± 1 W (∼50% maximal work capacity) for 45 min with catheters inserted in the brachial artery and both femoral veins. Biopsy samples obtained from vastus lateralis muscles of both legs before and after exercise were used for analysis of substrates, protein content and enzyme activities. During exercise, leg substrate utilization (respiratory quotient) did not differ between groups or legs. Leg fatty acid uptake was greater in older than in young men, and although young men demonstrated net leg glycerol release during exercise, older men showed net glycerol uptake. At baseline, IMTG, muscle pyruvate dehydrogenase complex activity and the protein content of adipose triglyceride lipase, acetyl‐CoA carboxylase 2 and AMP‐activated protein kinase (AMPK)γ3 were higher in young than in older men. Furthermore, adipose triglyceride lipase, plasma membrane‐associated fatty acid binding protein and AMPKγ3 subunit protein contents were lower and IMTG was higher in the immobilized than the contralateral leg in young and older men. Thus, immobilization and age did not affect substrate choice (respiratory quotient) during moderate exercise, but the whole‐leg and molecular differences in fatty acid mobilization could explain the age‐ and immobilization‐induced IMTG accumulation.
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Aging and disuse, even in the absence of insulin resistance, are associated with increased intramyocellular lipids.
“However, aging and disuse, even in the absence of insulin resistance are associated with increased IMCLs [57, 60–63].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [62]
Aging muscles lack the metabolic flexibility to process intramyocellular lipids in the way younger muscles do, leading to lipotoxicity and associated impairments.
“we suggest a hypothesis whereby aging muscles lack the metabolic flexibility to process the IMCLs in the way that younger muscles do [62, 65, 66], leading to lipotoxicity and its associated impairments.”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [62]
Muscle disuse leads to a shift away from lipid toward carbohydrate oxidation similar to that seen with old age, potentially compounding deficits in metabolic flexibility and leading to further intramyocellular lipid accumulation.
“Evidence suggests that muscle disuse leads to a shift away from lipid toward carbohydrate oxidation has been shown with muscle disuse [62, 72, 82] similar to that seen with old age, potentially compounding deficits in metabolic flexibility and leading to further IMCL accumulation.”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [62]
With imposed muscle disuse, normal resting lipid oxidation is disrupted and these conditions are associated with increased intramyocellular lipids.
“With imposed muscle disuse (e.g., bedrest, immobilization), normal resting lipid oxidation is disrupted and these conditions are also associated with increased IMCL [62, 72, 82].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [62]
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“Evidence suggests that muscle dis-use leads to a shift away from lipid toward carbohydrate oxidation has been shown with muscle disuse [62, 72, 82] similar to that seen with old age, potentially compounding deficits in metabolic flexibility and leading to further IMCL accumulation.”
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- Authors
- Vigelsø, A., Gram, M., Dybboe, R., Kuhlman, A. B., Prats, C., Greenhaff, P. L., Constantin‐Teodosiu, D., Birk, J. B., Wojtaszewski, J. F. P., Dela, F., & Helge, J. W.
- Affiliations
- University of Copenhagen (DK)
- University of Nottingham (GB)
- Corresponding author
- Vigelsø, A.
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2016-03-04
- Volume
- 594
- Issue
- 8
- Pages
- 2339-2358
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC4933116
- OpenAlex
- W2345561759
- Cited by
- 24
- References
- 71
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 1
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (acceptedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Ministério da Ciência, Tecnologia e Inovação
- Lundbeckfonden (R221-2016-1512)
- Nordea-fonden
- Novo Nordisk Fonden (NNF14OC0012009)
- Medical Research Council (MR/K00414X/1)
- Biotechnology and Biological Sciences Research Council (BB/I020713/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- physical inactivity, substrate utilization, moderate-intensity exercise, fatty acid uptake, glycerol metabolism, pyruvate dehydrogenase complex, adipose triglyceride lipase, acetyl-CoA carboxylase 2, AMPK, muscle lipid metabolism, skeletal muscle
- MeSH terms
- Acetyl-CoA Carboxylase, Aged, Aging, Humans, Leg, Lipase, Male, Restraint, Physical, Anaerobic Threshold, Exercise, Muscle, Skeletal, Carbohydrate Metabolism, Lipid Metabolism, AMP-Activated Protein Kinases, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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