Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia
Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ablation of Pax7+ muscle progenitor cells (MPC...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Cardiovascular Medicine |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1118738/full |
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| author | Hasan Abbas Hasan Abbas Hasan Abbas Lindsey A. Olivere Michael E. Padgett Cameron A. Schmidt Cameron A. Schmidt Brian F. Gilmore Timothy J. McCord Kevin W. Southerland Joseph M. McClung Joseph M. McClung Joseph M. McClung Christopher D. Kontos Christopher D. Kontos Christopher D. Kontos |
| author_facet | Hasan Abbas Hasan Abbas Hasan Abbas Lindsey A. Olivere Michael E. Padgett Cameron A. Schmidt Cameron A. Schmidt Brian F. Gilmore Timothy J. McCord Kevin W. Southerland Joseph M. McClung Joseph M. McClung Joseph M. McClung Christopher D. Kontos Christopher D. Kontos Christopher D. Kontos |
| author_sort | Hasan Abbas |
| collection | DOAJ |
| description | Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ablation of Pax7+ muscle progenitor cells (MPCs) in a model of hindlimb ischemia (HLI) inhibited muscle regeneration following ischemic injury, despite a lack of morphological or physiological changes in resting muscle. Compared to control mice (Pax7WT), the ischemic limb of Pax7-deficient mice (Pax7Δ) was unable to generate significant force 7 or 28 days after HLI. A significant increase in adipose was observed in the ischemic limb 28 days after HLI in Pax7Δ mice, which replaced functional muscle. Adipogenesis in Pax7Δ mice corresponded with a significant increase in PDGFRα+ fibro/adipogenic progenitors (FAPs). Inhibition of FAPs with batimastat decreased muscle adipose but increased fibrosis. In vitro, Pax7Δ MPCs failed to form myotubes but displayed increased adipogenesis. Skeletal muscle from patients with critical limb threatening ischemia displayed increased adipose in more ischemic regions of muscle, which corresponded with fewer satellite cells. Collectively, these data demonstrate that Pax7+ MPCs are required for muscle regeneration after ischemia and suggest that muscle regeneration may be an important therapeutic target in PAD. |
| first_indexed | 2024-04-10T06:20:48Z |
| format | Article |
| id | doaj.art-a35bd435f70c4f4abab32ab71391c845 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-04-10T06:20:48Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-a35bd435f70c4f4abab32ab71391c8452023-03-02T05:00:27ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2023-03-011010.3389/fcvm.2023.11187381118738Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemiaHasan Abbas0Hasan Abbas1Hasan Abbas2Lindsey A. Olivere3Michael E. Padgett4Cameron A. Schmidt5Cameron A. Schmidt6Brian F. Gilmore7Timothy J. McCord8Kevin W. Southerland9Joseph M. McClung10Joseph M. McClung11Joseph M. McClung12Christopher D. Kontos13Christopher D. Kontos14Christopher D. Kontos15Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United StatesDuke-NUS Medical School, Singapore, SingaporeDepartment of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, United StatesDuke University School of Medicine, Durham, NC, United StatesDepartment of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, United StatesDepartment of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesBrody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United StatesDepartment of Surgery, Duke University Medical Center, Durham, NC, United StatesDepartment of Cell Biology, Duke University School of Medicine, Durham, NC, United StatesDepartment of Surgery, Duke University Medical Center, Durham, NC, United StatesDepartment of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesBrody School of Medicine, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United StatesBrody School of Medicine, East Carolina Heart Institute, East Carolina University, Greenville, NC, United StatesDepartment of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United StatesDepartment of Medicine, Division of Cardiology, Duke University Medical Center, Durham, NC, United StatesDuke University School of Medicine, Durham, NC, United StatesSkeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ablation of Pax7+ muscle progenitor cells (MPCs) in a model of hindlimb ischemia (HLI) inhibited muscle regeneration following ischemic injury, despite a lack of morphological or physiological changes in resting muscle. Compared to control mice (Pax7WT), the ischemic limb of Pax7-deficient mice (Pax7Δ) was unable to generate significant force 7 or 28 days after HLI. A significant increase in adipose was observed in the ischemic limb 28 days after HLI in Pax7Δ mice, which replaced functional muscle. Adipogenesis in Pax7Δ mice corresponded with a significant increase in PDGFRα+ fibro/adipogenic progenitors (FAPs). Inhibition of FAPs with batimastat decreased muscle adipose but increased fibrosis. In vitro, Pax7Δ MPCs failed to form myotubes but displayed increased adipogenesis. Skeletal muscle from patients with critical limb threatening ischemia displayed increased adipose in more ischemic regions of muscle, which corresponded with fewer satellite cells. Collectively, these data demonstrate that Pax7+ MPCs are required for muscle regeneration after ischemia and suggest that muscle regeneration may be an important therapeutic target in PAD.https://www.frontiersin.org/articles/10.3389/fcvm.2023.1118738/fullperipheral artery diseasecritical limb threatening ischemiamuscle progenitor cellsskeletal muscle regenerationfibro/adipogenic progenitor cellshind limb ischemia |
| spellingShingle | Hasan Abbas Hasan Abbas Hasan Abbas Lindsey A. Olivere Michael E. Padgett Cameron A. Schmidt Cameron A. Schmidt Brian F. Gilmore Timothy J. McCord Kevin W. Southerland Joseph M. McClung Joseph M. McClung Joseph M. McClung Christopher D. Kontos Christopher D. Kontos Christopher D. Kontos Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia Frontiers in Cardiovascular Medicine peripheral artery disease critical limb threatening ischemia muscle progenitor cells skeletal muscle regeneration fibro/adipogenic progenitor cells hind limb ischemia |
| title | Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia |
| title_full | Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia |
| title_fullStr | Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia |
| title_full_unstemmed | Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia |
| title_short | Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia |
| title_sort | muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia |
| topic | peripheral artery disease critical limb threatening ischemia muscle progenitor cells skeletal muscle regeneration fibro/adipogenic progenitor cells hind limb ischemia |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2023.1118738/full |
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