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Identification and characterization of PDGFR?+ mesenchymal progenitors in human skeletal muscle.

ABSTRACT: Fatty and fibrous connective tissue formation is a hallmark of diseased skeletal muscle and deteriorates muscle function. We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In this study, we report the identification and characterization of a human counterpart to these progenitors. By using PDGFR? as a specific marker, mesenchymal progenitors can be identified in the interstitium and isolated from human skeletal muscle. PDGFR?(+) cells represent a cell population distinct from CD56(+) myogenic cells, and adipogenic and fibrogenic potentials were highly enriched in the PDGFR?(+) population. Activation of PDGFR? stimulates proliferation of PDGFR?(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFR?(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. Our results revealed the pathological relevance of PDGFR?(+) mesenchymal progenitors to human muscle diseases and provide a basis for developing therapeutic strategy to treat muscle diseases.

SUBMITTER: Uezumi A

PROVIDER: S-EPMC4001314 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle.

Uezumi A A Fukada S S Yamamoto N N Ikemoto-Uezumi M M Nakatani M M Morita M M Yamaguchi A A Yamada H H Nishino I I Hamada Y Y Tsuchida K K

Cell death & disease 20140417

Fatty and fibrous connective tissue formation is a hallmark of diseased skeletal muscle and deteriorates muscle function. We previously identified non-myogenic mesenchymal progenitors that contribute to adipogenesis and fibrogenesis in mouse skeletal muscle. In this study, we report the identification and characterization of a human counterpart to these progenitors. By using PDGFRα as a specific marker, mesenchymal progenitors can be identified in the interstitium and isolated from human skeleta ...[more]

PMID: 24743741

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Project description:BackgroundSarcopenia widely exists in elderly people and triggers numerous age-related events. The essential pathologic change lies in the increased intramuscular adipose tissue after aging with no exception to non-obese objects. Pim1 appears to be associated with adipogenic differentiation in recent studies, inspiring us to explore whether it regulates adipogenesis in aging muscles and affects sarcopenia.MethodsWild-type and Pim1 knockout C57/BL6J mice were randomized into young and old groups. Histo-pathological and molecular biological methods were applied to assess the intramuscular adipose tissue content, the atrophy and regeneration, and the expressions of Pim1 and adipogenic transcription factors. PDGFRα+ mesenchymal progenitors were separated and their replicative aging model were established. Different time of adipogenic induction and different amounts of Pim1 inhibitor were applied, after which the adipogenic potency were evaluated. The expressions of Pim1 and adipogenic transcription factors were measured through western blotting.ResultsThe aging mice demonstrated decreased forelimb grip strength (P = 0.0003), hanging impulse (P < 0.0001), exhaustive running time (P < 0.0001), tetanic force (P = 0.0298), lean mass (P = 0.0008), and percentage of gastrocnemius weight in body weight (P < 0.0001), which were improved by Pim1 knockout (P = 0.0015, P = 0.0222, P < 0.0001, P = 0.0444, P = 0.0004, and P = 0.0003, respectively). To elucidate the mechanisms, analyses showed that Pim1 knockout decreased the fat mass (P = 0.0005) and reduced the intramuscular adipose tissue content (P = 0.0008) by inhibiting the C/EBPδ pathway (P = 0.0067) in aging mice, resulting in increased cross-sectional area of all and fast muscle fibres (P = 0.0017 and 0.0024 respectively), decreased levels of MuRF 1 and atrogin 1 (P = 0.0001 and 0.0329 respectively), and decreased content of Pax7 at the basal state (P = 0.0055). In vitro, senescent PDGFRα+ mesenchymal progenitors showed significantly increased the intracellular adipose tissue content (OD510) compared with young cells after 6 days of adipogenic induction (P < 0.0001). The Pim1 expression was elevated during adipogenic differentiation, and Pim1 inhibition significantly reduced the OD510 in senescent cells (P = 0.0040) by inhibiting the C/EBPδ pathway (P = 0.0047).ConclusionsPim1 knockout exerted protective effects in sarcopenia by inhibiting the adipogenic differentiation of PDGFRα+ mesenchymal progenitors induced by C/EBPδ activation and thus reducing the intramuscular adipose tissue content in aging mice. These results provide a potential target for the treatment of sarcopenia.

Dataset Information

Identification and characterization of PDGFR?+ mesenchymal progenitors in human skeletal muscle.

Publications

Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle.

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