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Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity

ABSTRACT: Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity

PROVIDER: PRJNA747287 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15177952.fastq.gz	Fastqsanger.gz
	SRR15177953.fastq.gz	Fastqsanger.gz
	SRR15177954.fastq.gz	Fastqsanger.gz
	SRR15177955.fastq.gz	Fastqsanger.gz
	SRR15177956.fastq.gz	Fastqsanger.gz

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Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity

Project description: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 towards a slow MN identity. In muscle, NRTN increased capillary density, 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-1ɑ1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.

2021-11-30 | GSE180266 | GEO

Muscle-secreted neurturin couples fiber oxidative metabolism and slow motor neuron identity

Project description:Muscle-secreted neurturin couples fiber oxidative metabolism and slow motor neuron identity

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The secreted factor TSK maintains slow-twitch myofiber integrity and exercise endurance and contributes to muscle regeneration

Project description:Mammalian skeletal muscle contains heterogenous myofibers with different contractile and metabolic properties that sustain muscle mass and endurance capacity. The transcriptional regulators that govern these myofiber gene programs have been elucidated. However, the hormonal cues that direct the specification of myofiber types and muscle endurance remain largely unknown. Here we uncover the secreted factor Tsukushi (TSK) as an extracellular signal that is required for maintaining muscle mass, strength, and endurance capacity, and contributes to muscle regeneration. Mice lacking TSK exhibited reduced grip strength and impaired exercise capacity. Muscle transcriptomic analysis revealed that TSK deficiency results in a remarkably selective impairment in the expression of myofibrillar genes characteristic of slow-twitch muscle fibers that is associated with abnormal neuromuscular junction formation. AAV-mediated overexpression of TSK failed to rescue these myofiber defects in adult mice, suggesting that the effects of TSK on myofibers are likely restricted to certain developmental stages. Finally, mice lacking TSK exhibited diminished muscle regeneration following cardiotoxin-induced muscle injury. These findings support a crucial role of TSK as a hormonal cue in the regulation of contractile gene expression, endurance capacity, and muscle regeneration.

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The secreted factor TSK maintains slow-twitch myofiber integrity and exercise endurance and contributes to muscle regeneration

Project description:The secreted factor TSK maintains slow-twitch myofiber integrity and exercise endurance and contributes to muscle regeneration

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The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling

Project description:Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling that is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast TA. Here we use bulk RNA-seq to perform transcriptomic analysis of slow and fast mouse muscle. RNAseq analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1 pathway components. Moreover, Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including the IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.

2024-01-10 | GSE212352 | GEO

Muscle-secreted neurturin couples fiber oxidative metabolism and slow motor neuron identity

Project description:In this study we evaluate the effects of muscle-derived neurturin on skeletal muscle innervation, metabolism, and performance.

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The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy

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The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy

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The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy

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The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling

Project description:The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling

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