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Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE227077 | GEO | 2023/10/16

REPOSITORIES: GEO

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Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.

Project description:BackgroundChronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell-cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI.MethodsWe performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell-cell signaling interactions and differentiation trajectories.ResultsSingle-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries.ConclusionsCollectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

| S-EPMC10636829 | biostudies-literature

Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells [RNA-seq]

Project description:To validate the findings from scRNA-seq, we purified CD11b+/F480+ macrophages by FACS from the hind limb muscle of C57BL/6 (n=3) and BALB/c (n=2) mice at 3-days post HLI for bulk RNA-seq analysis We then performed gene expression profiling analysis using data obtained from RNA-seq of isolated macrophages from C57BL/6 and BALB/c mice at day 3 after HLI surgery.

2023-10-16 | GSE227076 | GEO

Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells [scRNA-seq]

Project description:To investigate the molecular mechanisms responsible for failed skeletal muscle repair in the Chronic limb threatening ischemia (CLTI) limb. We used single cell RNA sequencing (scRNA-seq) to profile the transcriptomes of the skeletal muscle specimens.

2023-10-16 | GSE227075 | GEO

Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells

Project description:Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells

| PRJNA943174 | ENA

Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells [scRNA-seq]

Project description:Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells [scRNA-seq]

| PRJNA943182 | ENA

Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells [RNA-seq]

Project description:Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells [RNA-seq]

| PRJNA943181 | ENA

MicroRNA-155 facilitates skeletal muscle regeneration by balancing pro- and anti-inflammatory macrophages.

Project description:Skeletal muscle has remarkable regeneration capacity and regenerates in response to injury. Muscle regeneration largely relies on muscle stem cells called satellite cells. Satellite cells normally remain quiescent, but in response to injury or exercise they become activated and proliferate, migrate, differentiate, and fuse to form multinucleate myofibers. Interestingly, the inflammatory process following injury and the activation of the myogenic program are highly coordinated, with myeloid cells having a central role in modulating satellite cell activation and regeneration. Here, we show that genetic deletion of microRNA-155 (miR-155) in mice substantially delays muscle regeneration. Surprisingly, miR-155 does not appear to directly regulate the proliferation or differentiation of satellite cells. Instead, miR-155 is highly expressed in myeloid cells, is essential for appropriate activation of myeloid cells, and regulates the balance between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages during skeletal muscle regeneration. Mechanistically, we found that miR-155 suppresses SOCS1, a negative regulator of the JAK-STAT signaling pathway, during the initial inflammatory response upon muscle injury. Our findings thus reveal a novel role of miR-155 in regulating initial immune responses during muscle regeneration and provide a novel miRNA target for improving muscle regeneration in degenerative muscle diseases.

| S-EPMC5143393 | biostudies-literature

Influence of sexual dimorphism on satellite cell regulation and inflammatory response during skeletal muscle regeneration.

Project description:After injury, skeletal muscle regenerates thanks to the key role of satellite cells (SC). The regeneration process is supported and coordinated by other cell types among which immune cells. Among the mechanisms involved in skeletal muscle regeneration, a sexual dimorphism, involving sex hormones and more particularly estrogens, has been suggested. However, the role of sexual dimorphism on skeletal muscle regeneration is not fully understood, likely to the use of various experimental settings in both animals and human. This review aims at addressing how sex and estrogens regulate both the SC and the inflammatory response during skeletal muscle regeneration by considering the different experimental designs used in both animal models (i.e., ovarian hormone deficiency, estrogen replacement or supplementation, treatments with estrogen receptors agonists/antagonists and models knockout for estrogen receptors) and human (hormone therapy replacement, pre vs. postmenopausal, menstrual cycle variation…).

| S-EPMC10555529 | biostudies-literature

PPAR? regulates satellite cell proliferation and skeletal muscle regeneration.

Project description:Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear receptors that play important roles in development and energy metabolism. Whereas PPAR? has been shown to regulate mitochondrial biosynthesis and slow-muscle fiber types, its function in skeletal muscle progenitors (satellite cells) is unknown. Since constitutive mutation of Ppar? leads to embryonic lethality, we sought to address this question by conditional knockout (cKO) of Ppar? using Myf5-Cre/Ppar?flox/flox alleles to ablate PPAR? in myogenic progenitor cells. Although Ppar?-cKO mice were born normally and initially displayed no difference in body weight, muscle size or muscle composition, they later developed metabolic syndrome, which manifested as increased body weight and reduced response to glucose challenge at age nine months. Ppar?-cKO mice had 40% fewer satellite cells than their wild-type littermates, and these satellite cells exhibited reduced growth kinetics and proliferation in vitro. Furthermore, regeneration of Ppar?-cKO muscles was impaired after cardiotoxin-induced injury. Gene expression analysis showed reduced expression of the Forkhead box class O transcription factor 1 (FoxO1) gene in Ppar?-cKO muscles under both quiescent and regenerating conditions, suggesting that PPAR? acts through FoxO1 in regulating muscle progenitor cells. These results support a function of PPAR? in regulating skeletal muscle metabolism and insulin sensitivity, and they establish a novel role of PPAR? in muscle progenitor cells and postnatal muscle regeneration.

| S-EPMC3223495 | biostudies-literature

Regeneration competent satellite cell niches in rat engineered skeletal muscle.

Project description:Satellite cells reside in defined niches and are activated upon skeletal muscle injury to facilitate regeneration. Mechanistic studies of skeletal muscle regeneration are hampered by the inability to faithfully simulate satellite cell biology in vitro. We sought to overcome this limitation by developing tissue engineered skeletal muscle (ESM) with (1) satellite cell niches and (2) the capacity to regenerate after injury. ESMs contained quiescent Pax7-positive satellite cells in morphologically defined niches. Satellite cells could be activated to repair (i) cardiotoxin and (ii) mechanical crush injuries. Activation of the Wnt-pathway was essential for muscle regeneration. Finally, muscle progenitors from the engineered niche developed de novo ESM in vitro and regenerated skeletal muscle after cardiotoxin-induced injury in vivo. We conclude that ESM with functional progenitor niches reminiscent of the in vivo satellite cell niches can be engineered in vitro. ESM may ultimately be exploited in disease modeling, drug screening, or muscle regeneration.

| S-EPMC6996344 | biostudies-literature

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