Human skeletal muscle fibroblasts, but not myogenic cells, readily undergo adipogenic differentiation

Agley, Chibeza C.; Rowlerson, A; Velloso, Cristiana P.; Lazarus, Norman R.; Harridge, Sdr

doi:10.1242/jcs.132563

Cited by 88 publications

(109 citation statements)

References 100 publications

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“…Analysing both polyclonal and monoclonal cell cultures, we could not identify any MP subpopulation with adipogenic potential. Our results further support previous work showing that MPs are committed to the myogenic fate30, 31, 49, 51 and that FAPs are the adipocyte precursor population residing in murine30, 31, 32, 52 and human24, 51, 53, 54 adult skeletal muscle. Although we cannot reject the hypothesis that a small subpopulation of satellite cells could form brown adipocytes—as shown by Yin et al 27.…”

Section: Discussionsupporting

confidence: 92%

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

Gorski

Mathes

Krützfeldt

2018

J cachexia sarcopenia muscle

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BackgroundIntramuscular fatty infiltration is generally associated with the accumulation of white adipocytes in skeletal muscle and unfavourable metabolic outcomes. It is, however, still unclear whether intramuscular adipocytes could also acquire a brown‐like phenotype. Here, we detected intramuscular expression of brown adipocyte markers during fatty infiltration in an obesity‐resistant mouse strain and extensively compared the potential of two different stem cell populations residing in skeletal muscle to differentiate into brown‐like adipocytes.MethodsFatty infiltration was induced using intramuscular glycerol or cardiotoxin injection in the tibialis anterior muscles of young or aged 129S6/SvEvTac (Sv/129) mice or interleukin‐6 (IL‐6) knockout mice, and the expression of general and brown adipocyte markers was assessed after 4 weeks. Fibro/adipogenic progenitors (FAPs) and myogenic progenitors were prospectively isolated using fluorescence‐activated cell sorting from skeletal muscle of male and female C57Bl6/6J and Sv/129 mice, and monoclonal and polyclonal cultures were treated with brown adipogenic medium. Additionally, FAPs were differentiated with medium supplemented or not with triiodothyronine.ResultsAlthough skeletal muscle expression of uncoupling protein 1 (Ucp1) was barely detectable in uninjected tibialis anterior muscle, it was drastically induced following intramuscular adipogenesis in Sv/129 mice and further increased in response to beta 3‐adrenergic stimulation. Intramuscular Ucp1 expression did not depend on IL‐6 and was preserved in aged skeletal muscle. Myogenic progenitors did not form adipocytes neither in polyclonal nor monoclonal cultures. Fibro/adipogenic progenitors, on the other hand, readily differentiated into brown‐like, UCP1+ adipocytes. Uncoupling protein 1 expression in differentiated FAPs was regulated by genetic background, sex, and triiodothyronine treatment independently of adipogenic differentiation levels.ConclusionsIntramuscular adipogenesis is associated with increased Ucp1 expression in skeletal muscle from obesity‐resistant mice. Fibro/adipogenic progenitors provide a likely source for intramuscular adipocytes expressing UCP1 under control of both genetic and hormonal factors. Therefore, FAPs constitute a possible target for therapies aiming at the browning of intramuscular adipose tissue and the metabolic improvement of skeletal muscle affected by fatty infiltration.

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Section: Discussionsupporting

confidence: 92%

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

Gorski

Mathes

Krützfeldt

2018

J cachexia sarcopenia muscle

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“…With regard to the in vitro experiments, the CD56 magnetic sorting technique employed to separate human myogenic from non‐myogenic cells has also been used by others, where the negative fraction has been shown to predominantly comprise cells expressing fibroblast markers, such as TE‐7, and that were negative for desmin (Agley et al . ), as we also observed. While we cannot completely rule out the presence of other non‐myogenic cells (e.g.…”

Section: Discussionsupporting

confidence: 89%

Human skeletal muscle fibroblasts stimulate in vitro myogenesis and in vivo muscle regeneration

Mackey

Magnan

Chazaud

et al. 2017

The Journal of Physiology

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Accumulation of skeletal muscle extracellular matrix is an unfavourable characteristic of many muscle diseases, muscle injury and sarcopenia. In addition to the indispensable role satellite cells play in muscle regeneration, there is emerging evidence in rodents for a regulatory influence on fibroblast activity. However, the influence of fibroblasts on satellite cells and muscle regeneration in humans is unknown. The purpose of this study was to investigate this in vitro and during in vivo regeneration in humans. Following a muscle injury protocol in young healthy men (n = 7), the number of fibroblasts (TCF7L2+), satellite cells (Pax7+), differentiating myogenic cells (myogenin+) and regenerating fibres (neonatal/embryonic myosin+) was determined from biopsy cross-sections. Fibroblasts and myogenic precursor cells (MPCs) were also isolated from human skeletal muscle (n = 4) and co-cultured using different cell ratios, with the two cell populations either in direct contact with each other or separated by a permeable membrane. MPC proliferation, differentiation and fusion were assessed from cells stained for BrdU, desmin and myogenin. On biopsy cross-sections, fibroblast number was seen to increase, along with myogenic cell number, by d7 and increase further by d30, where fibroblasts were observed to be preferentially located immediately surrounding regenerating muscle fibres. In vitro, the presence of fibroblasts in direct contact with MPCs was found to moderately stimulate MPC proliferation and strongly stimulate both MPC differentiation and MPC fusion. It thus appears, in humans, that fibroblasts exert a strong positive regulatory influence on MPC activity, in line with observations during in vivo skeletal muscle regeneration.

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“…To assure that the loss of myogenic gene expression observed in the T2DM cells was not due to a higher degree of infiltration by non-muscle cell types in this group, flow cytometry was applied. CD56, which is specifically displayed on human myoblast but not on adipocytes or fibroblasts [29], [30], was expressed on all cell cultures used in the study at either high or intermediate levels (Figure 1F,G). All cells were also CD90-positive, reflecting their mesenchymal origin [31], whereas cells were negative for the hematopoietic marker CD45 and the endothelial marker CD31 (Figure 1F).…”

Section: Resultsmentioning

confidence: 97%

Dysregulation of a novel miR-23b/27b-p53 axis impairs muscle stem cell differentiation of humans with type 2 diabetes

Henriksen

Davidsen

Pedersen

et al. 2017

Molecular Metabolism

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ObjectiveMicroRNAs (miRNAs) are increasingly recognized as fine-tuning regulators of metabolism, and are dysregulated in several disease conditions. With their capacity to rapidly change gene expression, miRNAs are also important regulators of development and cell differentiation. In the current study, we describe an impaired myogenic capacity of muscle stem cells isolated from humans with type 2 diabetes (T2DM) and assess whether this phenotype is regulated by miRNAs.MethodsWe measured global miRNA expression during in vitro differentiation of muscle stem cells derived from T2DM patients and healthy controls.ResultsThe mir-23b/27b cluster was downregulated in the cells of the patients, and a pro-myogenic effect of these miRNAs was mediated through the p53 pathway, which was concordantly dysregulated in the muscle cells derived from humans with T2DM.ConclusionsOur results indicate that we have identified a novel pathway for coordination of myogenesis, the miR-23b/27b-p53 axis that, when dysregulated, potentially contributes to a sustained muscular dysfunction in T2DM.

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Human skeletal muscle fibroblasts, but not myogenic cells, readily undergo adipogenic differentiation

Cited by 88 publications

References 100 publications

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

Human skeletal muscle fibroblasts stimulate in vitro myogenesis and in vivo muscle regeneration

Dysregulation of a novel miR-23b/27b-p53 axis impairs muscle stem cell differentiation of humans with type 2 diabetes

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