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Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism

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Abstract

Adult stem cells are known to have a finite replication potential. Muscle biopsy-derived human satellite cells (SCs) were grown at different passages and differentiated to human myotubes in culture to analyze the functional state of various carbohydrate and lipid metabolic pathways. As the proliferative potential of myoblasts decreased dramatically with passage number, a number of cellular functions were altered: the capacity of myoblasts to fuse and differentiate into myotubes was reduced, and metabolic processes in myotubes such as glucose uptake, glycogen synthesis, glucose oxidation and fatty acid β-oxidation became gradually impaired. Upon insulin stimulation, glucose uptake and glycogen synthesis increased but as the cellular proliferative capacity became gradually exhausted, the response dropped concomitantly. Palmitic acid incorporation into lipids in myotubes decreased with passage number and could be explained by reduced incorporation into diacyl- and triacylglycerols. The levels of long-chain acyl-CoA esters decreased with increased passage number. Late-passage, non-proliferating, myoblast cultures showed strong senescence-associated β-galactosidase activity indicating that the observed metabolic defects accompany the induction of a senescent state. The main function of SCs is regeneration and skeletal muscle-build up. Thus, the metabolic defects observed during aging of SC-derived myotubes could have a role in sarcopenia, the gradual age-related loss of muscle mass and strength.

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Abbreviations

ASM:

Acid soluble metabolites

BSA:

Bovine serum albumin

CE:

Cholesteryl esters

CPT:

Carnitine palmitoyltransferase

DAG:

Diacylglycerol

FCS:

Fetal calf serum

FFA:

Free fatty acids

GIR:

Glucose infusion rates

HI:

High insulin concentration

HPLC:

High-pressure liquid chromatography

LCA-CoA:

Long-chain acyl-CoA esters

PA:

Palmitic acid

PL:

Phospholipids

ROS:

Reactive oxygen species

SA-βGal:

Senescence-associated beta-galactosidase

SC:

Satellite cells

TAG:

Triacylglycerol

TCA:

Tricarboxylic acid

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Acknowledgments

Irene Lynfort and Karin Dyrgaard provided excellent technical assistance. Kurt Højlund and Klaus Levin are thanked for muscle biopsies. The present work was supported by the Lundbeck Foundation, the University of Southern Denmark and Odense University Hospital (J.O.N.). The Danish Medical Research Council and the Novo Nordisk Foundation are thanked for financial support (M.G.).

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Authors and Affiliations

  1. Center for Stem Cell Treatment, Department of Clinical Immunology, Odense University Hospital & University of Southern Denmark, Odense, Denmark

    Jan O. Nehlin

  2. Department of Clinical Immunology, Odense University Hospital & University of Southern Denmark, Sdr. Boulevard 29, DK-5000, Odense, Denmark

    Jan O. Nehlin

  3. Laboratory of Molecular Physiology, Department of Pathology and Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark

    Marlene Just & Michael Gaster

  4. Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway

    Arild C. Rustan

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  1. Jan O. Nehlin
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Correspondence to Jan O. Nehlin.

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Nehlin, J.O., Just, M., Rustan, A.C. et al. Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism. Biogerontology 12, 349–365 (2011). https://doi.org/10.1007/s10522-011-9336-5

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