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Metabolic and Transcriptional Changes in Cultured Muscle Stem Cells from Low Birth Weight Subjects
Ninna S Hansen1, Line Hjort1, Christa Broholm1
1Department of Endocrinology, Diabetes, and Metabolism (N.S.H., L.H., C.B., L.G., M.S., S.W.J., A.V.), Rigshospitalet, 2200 Copenhagen, Denmark; Faculty of Health and Medical Sciences (N.S.H., L.H., A.V.) University of Copenhagen, 1165 Copenhagen, Denmark; The Danish Diabetes Academy (L.H.), 5000 Odense, Denmark; Steno Diabetes Center A/S (B.M., S.W.J.), 2820 Gentofte, Denmark; The August Center (M.F., J.F.P.W.), Department of Nutrition, Exercise, and Sports, University of Copenhagen, 2200 Copenhagen, Denmark; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research (B.K.P.), Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2200 Copenhagen, Denmark; Center for Diabetes Research (B.M.), Gentofte Hospital, University of Copenhagen, 2200 Copenhagen, Denmark; and Novo Nordisk A/S (H.S.S.), 2880 Copenhagen, Denmark.
Insights
Individuals born with low birth weight (LBW) exhibit altered muscle stem cell function, contributing to an increased risk of type 2 diabetes (T2D). These findings highlight intrinsic defects in muscle stem cells from LBW individuals.
Area of Science:
- Cell Biology
- Metabolic Diseases
- Developmental Biology
Background:
- Low birth weight (LBW) is linked to an increased risk of developing type 2 diabetes (T2D) later in life.
- Developmental programming of human muscle stem cells may underlie this association.
- Immature muscle stem cell functions, including abnormal differentiation and metabolic capacity, are hypothesized to connect LBW with T2D risk.
Purpose of the Study:
- To investigate the functional characteristics of muscle stem cells in individuals born with LBW.
- To determine if altered muscle stem cell differentiation and metabolic function in LBW individuals contribute to T2D risk.
Main Methods:
- Recruited 23 young men with LBW and 16 age-matched controls with normal birth weight.
- Isolated and cultured primary muscle stem cells (satellite cells) into myotubes.
- Assessed glucose uptake, insulin signaling, myotube maturity markers, DNA methylation, and mitochondrial gene expression.
Main Results:
- Myotubes from LBW individuals showed reduced glucose uptake and lower levels of glucose transporters (GLUT1, GLUT4).
- Key myogenic differentiation markers (myogenin, MYH1, MYH2) were decreased in LBW myotubes.
- Mitochondrial gene expression (PGC-1α, COX7A) was also reduced in LBW myotubes, independent of DNA methylation changes.
Conclusions:
- Cultured primary satellite cells from LBW individuals exhibit persistent transcriptional and metabolic alterations.
- These findings suggest an intrinsic defect in muscle stem cells of LBW individuals, potentially contributing to T2D risk.
Context/Objective:
Developmental programming of human muscle stem cells could in part explain why individuals born with low birth weight (LBW) have an increased risk of developing type 2 diabetes (T2D) later in life. We hypothesized that immature muscle stem cell functions including abnormal differentiation potential and metabolic function could link LBW with the risk of developing T2D. Design/Settings/Participants: We recruited 23 young men with LBW and 16 age-matched control subjects with normal birth weight. Biopsies were obtained from vastus lateralis, and muscle stem cells were isolated and cultured into fully differentiated myotubes.
Main Outcome Measures:
We studied glucose uptake, glucose transporters, insulin signaling, key transcriptional markers of myotube maturity, selected site-specific DNA methylation, and mitochondrial gene expression.
Results:
We found reduced glucose uptake as well as decreased levels of glucose transporter-1 and -4 mRNA and of the Akt substrate of 160-kDa mRNA and protein in myotubes from LBW individuals compared with normal birth weight individuals. The myogenic differentiation markers, myogenin and myosin heavy chain 1 and 2, were decreased during late differentiation in LBW myotubes. Additionally, mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α and cytochrome c oxidase polypeptide 7A were reduced in LBW myotubes. Decreased gene expression was not explained by changes in DNA methylation levels.
Conclusion:
We demonstrate transcriptional and metabolic alterations in cultured primary satellite cells isolated from LBW individuals after several cell divisions, pointing toward a retained intrinsic defect conserved in these myotubes.
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