| 1. |
- Correia, Jorge C., et al.
(författare)
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Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
- 2021
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 33:11, s. 2215-2230
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Tidskriftsartikel (refereegranskat)abstract
- Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1a1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.
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| 2. |
- Dias, David O., et al.
(författare)
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Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
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| 3. |
- Kelahmetoglu, Yildiz
(författare)
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From brain to muscle and back : novel approaches to harness the benefits of exercise
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As the world population is growing older and more sedentary every day, the need for new approaches to combat chronic diseases grows steadily. Physical exercise improves health and reduces the risk of developing a plethora of chronic diseases. This body of work aims to investigate the molecular mechanisms underlying the neuronal and muscle function, their interaction and the potential signals that mediate this communication. To gain more insight into neurodegeneration, in paper I, we used a mouse model of Alzheimer’s disease and examined the mechanisms generating amyloid plaques. We discovered that Presenilin 1 (PS1), the key player of the enzyme responsible for generating the pathogenic peptides that make up the plaques, can play a dual role. Upon phosphorylation at a specific site, PS1 can facilitate the degradation of the substrate that would otherwise be cleaved to generate toxic amyloid peptides. This function ultimately reduces soluble amyloid peptide levels as well as the plaque burden. Overall this study extends our understanding of neurodegenerative processes and proposes a new target for intervention. In paper II, we investigated the transcriptional signatures of inherent and acquired exercise capacity in the skeletal muscle using uniquely developed rodent models. Our results associate high exercise capacity with angiogenesis and oxygenation while low exercise capacity profile reflects gene programs related to inflammation and cardiovascular disease. We interrogated the transcriptome data for potential upstream regulators and also secreted factors that can mediate exercise capacity and response. Finally, we compared the rat transcriptomic signatures with those of humans and identified an overlapping set of genes. In paper III, we explored the biological function of a muscle-secreted factor called Neurturin (NRTN). Transgenic animals overexpressing NRTN in skeletal muscle are leaner and more glucose tolerant than controls. Their muscles exhibit increased oxidative metabolism and vascularization. We observed a NRTN-induced remodelling in neuromuscular junction morphology and discovered that NRTN can promote a slow motor neuron identity and reduce markers for fast-motor neurons. Functionally, muscle-specific overexpression of NRTN enhances endurance performance and improves motor coordination. Systemic delivery at the adult stage could achieve an improvement in glucose metabolism and also recapitulate the improved motor coordination. We propose NRTN as a myokine with therapeutic promise for metabolic dysfunction and neuromuscular diseases.
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