The secreted factor TSK maintains slow-twitch myofiber integrity and exercise endurance and contributes to muscle regeneration
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ABSTRACT:
PROVIDER: PRJNA794748 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17446827.fastq.gz | Fastqsanger.gz | |||
| SRR17446828.fastq.gz | Fastqsanger.gz | |||
| SRR17446829.fastq.gz | Fastqsanger.gz | |||
| SRR17446830.fastq.gz | Fastqsanger.gz | |||
| SRR17446831.fastq.gz | Fastqsanger.gz |
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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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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.
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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 that 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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Project description:Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.
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