Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis

Marinković, Milica; Fuoco, Claudia; Sacco, Francesca; Perpetuini, Andrea Cerquone; Giuliani, Giulio; Micarelli, Elisa; Pavlidou, Theodora; Petrilli, Lucia Lisa; Reggio, Alessio; Riccio, Federica; Spada, Filomena; Vumbaca, Simone; Zuccotti, Alessandro; Castagnoli, Luisa; Mann, Matthias; Gargioli, Cesare

doi:10.26508/lsa.201900437

Cited by 42 publications

(82 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, shear stress‐induced release of NO from endothelial cells may inhibit adipogenesis, as it was shown to repress PPARγ promoter activity in FAP . Interestingly, previous reports have shown that nutrient availability and cellular metabolic programs also influence the process of FAP differentiation, suggesting that altered fatty acid availability in HF diet‐fed mice may have shifted the differentiation potential of these cells. Further investigation into the causal relationships between blood flow, fatty acid oxidation and fibrosis/adipogenesis within muscle recovering from ischaemic damage will be valuable in establishing conditions that promote improved regeneration.…”

Section: Discussionmentioning

confidence: 99%

High‐fat diet pre‐conditioning improves microvascular remodelling during regeneration of ischaemic mouse skeletal muscle

et al. 2020

View full text Add to dashboard Cite

Aim Critical limb ischaemia (CLI) is characterized by inadequate angiogenesis, arteriolar remodelling and chronic myopathy, which are most severe in type 2 diabetic patients. Hypertriglyceridaemia, commonly observed in these patients, compromises macrovascular function. However, the effects of high‐fat diet‐induced increases in circulating lipids on microvascular remodelling are not established. Here, we investigated if high‐fat diet would mimic the detrimental effect of type 2 diabetes on post‐ischaemia vascular remodelling and muscle regeneration, using a mouse model of hindlimb ischaemia. Methods Male C57Bl6/J mice were fed with normal or high‐fat diets for 8 weeks prior to unilateral femoral artery ligation. Laser doppler imaging was used to assess limb perfusion recovery. Vascular recovery, inflammation, myofibre regeneration and fibrosis were assessed at 4 or 14 days post‐ligation by histology and RNA analyses. Capillary‐level haemodynamics were assessed by intravital microscopy of control and regenerating muscles 14 days post‐ligation. Results High‐fat diet increased muscle succinate dehydrogenase activity and capillary‐level oxygen supply. At 4 days post‐ligation, no diet differences were detected in muscle damage, inflammatory infiltration or capillary activation. At 14 days post‐ligation, high fat‐fed mice displayed accelerated limb blood flow recovery, elevated capillary and arteriole densities as well as greater red blood cell supply rates and capillary‐level oxygen supply. Regenerating muscles from high fat‐fed mice displayed lower interstitial fat and collagen deposition. Conclusion The muscle‐level adaptations to high‐fat diet improved multiple aspects of muscle recovery in response to ischaemia and did not recapitulate the worse outcomes seen in diabetic CLI patients.

show abstract

Section: Discussionmentioning

confidence: 99%

High‐fat diet pre‐conditioning improves microvascular remodelling during regeneration of ischaemic mouse skeletal muscle

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In the healthy skeletal muscle, a balance is maintained between these myogenic progenitors and the FAPs, and the FAPs are believed to aid in muscle regeneration [28,29]. Kozlowska et al showed that MSCs from the healthy skeletal muscles have the limited adipogenic potential [30], and Marinkovic et al showed that seeding purified skeletal muscle stem cells and FAPs in co-culture at a 1: 1 ratio inhibits lipid droplet formation even under adipogenic conditions [31]. Aging can cause changes in skeletal muscle progenitor cells (e.g., decreased numbers, senescence).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture

et al. 2020

View full text Add to dashboard Cite

Background: Mesenchymal stem/stromal cells (MSCs) can replenish the aged cells of the musculoskeletal system in adult life. Stem cell exhaustion and decrease in their regenerative potential have been suggested to be hallmarks of aging. Here, we investigated whether muscle-and bone-derived MSCs of patients with osteoarthritis and osteoporosis are affected by this exhaustion, compared to healthy donors. Methods: Patients with primary osteoarthritis, femoral neck fractures due to osteoporosis, and healthy donors (controls) were included. MSCs were isolated from the skeletal muscle and subchondral bone from each patient and compared using ex vivo and in vitro analyses, including immunophenotyping, colony-forming unit fibroblast assays, growth kinetics, cell senescence, multilineage potential, and MSC marker gene expression profiling. Results: Freshly isolated cells from muscle from patients with osteoarthritis showed a lower proportion of CD45/ CD19/CD14/CD34-negative cells compared to patients with osteoporosis and healthy donors. Freshly isolated muscle cells from patients with osteoarthritis and osteoporosis also showed higher clonogenicity compared to healthy donors. MSCs from both tissues of osteoarthritis patients showed significantly reduced osteogenesis and MSCs from the bone also reduced adipogenesis. Chondrogenic pellet diameter was reduced in bone-derived MSCs from both patient groups compared to healthy donors. A significant positive correlation was observed between adipogenesis and CD271 expression in muscle-derived MSCs. CD73 was significantly lower in bone-derived MSCs from osteoarthritis patients, compared to osteoporosis patients. Gene expression profiling showed significantly lower expression of MSC marker gene leptin receptor, LEPR, previously identified as the major source of the bone and adipocytes in the adult bone marrow, in bone-derived MSCs from patients with osteoarthritis in comparison with osteoporotic patients and healthy donors.

show abstract

“…We have recently applied high-resolution mass spectrometry (MS)-based proteomics to characterize the changes in the FAP proteome upon acute (cardiotoxin) or chronic injury (Marinkovic et al, 2019). This unbiased strategy revealed that FAPs from mdx mice are also characterized by a significant reduction of mitochondrial metabolic enzymes, accompanied by an increased expression of glycolytic proteins (Marinkovic et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

et al. 2020

Self Cite

View full text Add to dashboard Cite

In Duchenne muscular dystrophy (DMD), the absence of the dystrophin protein causes a variety of poorly understood secondary effects. Notably, muscle fibers of dystrophic individuals are characterized by mitochondrial dysfunctions, as revealed by a reduced ATP production rate and by defective oxidative phosphorylation. Here, we show that in a mouse model of DMD (mdx), fibro/adipogenic progenitors (FAPs) are characterized by a dysfunctional mitochondrial metabolism which correlates with increased adipogenic potential. Using high-sensitivity mass spectrometry–based proteomics, we report that a short-term high-fat diet (HFD) reprograms dystrophic FAP metabolism in vivo. By combining our proteomic dataset with a literature-derived signaling network, we revealed that HFD modulates the β-catenin–follistatin axis. These changes are accompanied by significant amelioration of the histological phenotype in dystrophic mice. Transplantation of purified FAPs from HFD-fed mice into the muscles of dystrophic recipients demonstrates that modulation of FAP metabolism can be functional to ameliorate the dystrophic phenotype. Our study supports metabolic reprogramming of muscle interstitial progenitor cells as a novel approach to alleviate some of the adverse outcomes of DMD.

show abstract

Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis

Cited by 42 publications

References 68 publications

High‐fat diet pre‐conditioning improves microvascular remodelling during regeneration of ischaemic mouse skeletal muscle

High‐fat diet pre‐conditioning improves microvascular remodelling during regeneration of ischaemic mouse skeletal muscle

Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture

Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

Contact Info

Product

Resources

About