TAK1 is essential for growth and maintenance of skeletal muscle mass
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA413137 | ENA |
REPOSITORIES: ENA
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Project description:Our results demonstrate that targeted deletion of TAK1 inhibits muscle growth during post-natal development period. Inactivation of TAK1 also causes muscle wasting in adult mice. TAK1 regulates expression of a number of molecules and signaling pathways which mediate growth and maintenance of skeletal muscle.
2018-02-28 | GSE104586 | GEO
Project description:In this study, we show that muscle-specific inactivation of FBXW7 elicits striking defects in postprandial glucose metabolism and failure to maintain skeletal muscle mass in adult mice. Further, mice lacking FBXW7 exhibited impaired endurance capacity and exacerbated HFD-induced insulin resistance and postprandial hyperglycemia. At the mechanistic level, RNAseq and quantitative proteomic analysis revealed global effects of FBXW7 deficiency on skeletal muscle transcriptome and proteome. This work illustrates a prominent role of FBXW7 in integrating postprandial nutritional signals to coordinate glucose metabolism and muscle mass maintenance.
2024-06-21 | GSE140503 | GEO
Project description:FBXW7 coordinates postprandial muscle glucose metabolism and maintenance of skeletal muscle mass
| PRJNA589977 | ENA
Project description:The maintenance of skeletal muscle mass is critically dependent upon mitochondrial quality control, including balanced mitochondrial dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a key mediator of mitochondrial fission, plays an important role in these processes. However, the precise mechanisms by which Drp1 regulates mitochondrial integrity and muscle mass remain inadequately understood. Here, we show that acute Drp1 deletion from skeletal muscle impairs mitochondrial activity, increases Parkin-mediated mitophagy, progressively reduces mitochondrial DNA (mtDNA) content, and ultimately causes severe muscle atrophy. Interestingly, dual deletion of Drp1 and Parkin from skeletal muscle restored mtDNA content, but did not prevent muscle loss. Mechanistically, Drp1 deletion disrupted mitochondrial respiratory chain activity, which suppressed extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and downregulated the nuclear receptor subfamily 4 group member 1 (Nur77), a regulator of muscle quality. Finally, clenbuterol, a β2-adrenergic receptor agonist, activated Erk1/2 signaling, restored Nur77 expression, and rescued muscle atrophy. Collectively, our findings identify a Drp1-Erk1/2-Nur77 signaling axis that connects mitochondrial integrity to the preservation of skeletal muscle mass and represents a potential therapeutic avenue for muscle degeneration in mitochondrial and metabolic disorders.
2025-12-08 | GSE295479 | GEO
Project description:Rhabdomyosarcoma (RMS) is a malignant soft tissue sarcoma with a skeletal muscle phenotype, accounting for approximately 50% of all pediatric soft tissue sarcomas and 8% of all childhood cancers. Although RMS cells express myogenic regulatory factors, they fail to undergo terminal differentiation into mature muscle cells. Transforming growth factor β-activated kinase 1 (TAK1) is a major signaling protein that activates multiple intracellular pathways in response to growth factors, cytokines, and microbial products. Emerging evidence suggests that TAK1 is also an important regulator of self-renewal, proliferation, and differentiation of muscle progenitor cells. However, the role and mechanisms of action of TAK1 in RMS remain completely unknown. In this study, we demonstrate that TAK1 expression and activity are markedly elevated in a panel of RMS cell lines and in patient tumor specimens. Reverse phase protein array (RPPA) analyses revealed that TAK1 regulates the expression and activity of many molecules involved in cell cycle control, cell proliferation, and oncogenic signaling. Genetic knockdown or pharmacological inhibition of TAK1 suppresses RMS cell proliferation, migration, and invasiveness, while also promoting terminal myogenic differentiation. TAK1 inhibits differentiation in RMS, at least in part, through up-regulating YAP1 signaling. Our results also demonstrate that inducible knockdown of TAK1 in human RMS xenografts retards tumor growth and enhances myogenic differentiation in vivo. Collectively, these findings uncover a previously unrecognized role for TAK1 in RMS growth and differentiation, and suggest that TAK1 can be a potential therapeutic target for the treatment of RMS.
2025-12-16 | GSE313525 | GEO
Project description:Homeostatic control of dendritic cell (DC) survival is crucial for a productive adaptive immune response, but the molecular mechanism is not well defined. Moreover, how DCs influence homeostasis of the immune system under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report here that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells diminished DC populations, especially the CD8+ and CD103+ DC subsets in the lymphoid and non-lymphoid organs, respectively. This was associated with increased apoptosis of DCs, whereas DC proliferation and differentiation from precursors appeared largely normal. In addition, acute deletion of TAK1 caused DC apoptosis, indicating a direct role of TAK1 in actively maintaining DC survival. TAK1 deficiency impaired activities of the pro-survival NF-kB and AKT pathways but upregulated expression of the pro-apoptotic molecule Bim. Under steady state, loss of TAK1 in DCs resulted in a myeloid proliferative disorder, and altered homeostasis of T cells. In response to antigen stimulation, TAK1-deficient DCs were impaired for T cell priming and regulatory T cell generation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system RNA extracted from three replicate samples of wild-type and Map3k7 (TAK1) knockout dendritic cells was analyzed on Affymetrix gene expression arrays
2012-01-23 | E-GEOD-34417 | biostudies-arrayexpress
Project description:Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human-PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the higher binding affinity of TAK1 and p38IP for sequential polyUb binding by TAB2 and TAK1, respectively. Moreover, p38IP specifically scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.
2020-04-30 | PXD018330 | Pride
Project description:Homeostatic control of dendritic cell (DC) survival is crucial for a productive adaptive immune response, but the molecular mechanism is not well defined. Moreover, how DCs influence homeostasis of the immune system under steady state remains unclear. Combining DC-specific and inducible deletion systems, we report here that the kinase TAK1 is an essential regulator of DC survival and immune system homeostasis and function. Deficiency of TAK1 in CD11c+ cells diminished DC populations, especially the CD8+ and CD103+ DC subsets in the lymphoid and non-lymphoid organs, respectively. This was associated with increased apoptosis of DCs, whereas DC proliferation and differentiation from precursors appeared largely normal. In addition, acute deletion of TAK1 caused DC apoptosis, indicating a direct role of TAK1 in actively maintaining DC survival. TAK1 deficiency impaired activities of the pro-survival NF-kB and AKT pathways but upregulated expression of the pro-apoptotic molecule Bim. Under steady state, loss of TAK1 in DCs resulted in a myeloid proliferative disorder, and altered homeostasis of T cells. In response to antigen stimulation, TAK1-deficient DCs were impaired for T cell priming and regulatory T cell generation. Therefore, TAK1 orchestrates a pro-survival checkpoint in DCs that affects the homeostasis and function of the immune system
2012-01-23 | GSE34417 | GEO
Project description:We propose that the Muscle-Brain-Gut axis regulates skeletal muscle mass through the defined mechanism.
2023-12-11 | GSE249324 | GEO
Project description:The vitamin D receptor (VDR) autonomously regulates skeletal muscle mass
| PRJNA433878 | ENA