Biology subjects

Tomaz da Silva, M.

Publications and source records attributed to Tomaz da Silva, M..

10 recordsLinked to original sources

bioRxiv2026

TAK1 regulates skeletal muscle mass, hypertrophic signaling, and metabolic homeostasis in male and female mice

Skeletal muscle is the most abundant tissue in the human body and is essential for locomotion and the regulation of whole-body metabolism. The maintenance of skeletal muscle mass is essential for health, yet the molecular and signaling mechanisms that control skeletal muscle mass remain poorly understood. Transforming growth factor-{beta}-activated kinase 1 (TAK1) is a key signaling protein that regulates multiple intracellular pathways. Recent studies have demonstrated that TAK1 is a critical regulator of skeletal muscle mass. However, the mechanisms by which TAK1 regulates muscle mass and whether its role is sex dependent remain incompletely understood. In this study, we show that targeted inactivation of TAK1 induces muscle atrophy more rapidly in male than in female mice. Loss of TAK1 activity also abolished mechanical overload-induced phosphorylation of p70S6K and rpS6, and the induction of myofiber hypertrophy in both sexes. RNA-Seq analysis further revealed that TAK1 inactivation in skeletal muscle disrupts the gene expression of various molecules involved in catabolic processes, calcium signaling, muscle structure development, and aerobic respiration. Moreover, TAK1 inactivation impairs fatty acid oxidation and promotes lipid accumulation in skeletal muscle of adult mice in a sex-independent manner. Collectively, our findings demonstrate that TAK1 regulates skeletal muscle mass and growth by coordinating distinct intracellular pathways in both male and female mice.

physiology↗

bioRxiv2025

Targeting the IRE1α/XBP1 Signaling Axis Suppresses Rhabdomyosarcoma Growth and Promotes Myogenic Differentiation

Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma arising from mesenchymal progenitors with skeletal muscle features. The unfolded protein response (UPR) maintains proteostasis during endoplasmic reticulum stress, with the IRE1-XBP1 axis representing a key signaling branch. Here, we demonstrate that components of this pathway are significantly upregulated in RMS cell lines and primary tumors. Genetic or pharmacological inhibition of IRE1 or spliced XBP1 (sXBP1) suppresses cell proliferation, promotes terminal myogenic differentiation, and enhances vincristine-induced cytotoxicity in RMS cells. Silencing of sXBP1 further reduces the cancer stem-like cell population and impairs migration and invasion. Mechanistically, IRE1-XBP1 signaling promotes RMS progression through sXBP1-dependent upregulation of BMPR1A and subsequent activation of BMP-SMAD1 signaling. Consistently, inducible knockdown of sXBP1 or pharmacological inhibition of IRE1 endonuclease activity significantly attenuates xenograft RMS growth. Collectively, these findings identify the IRE1-XBP1 axis as a critical regulator of RMS growth, differentiation, and chemoresistance, and support its therapeutic targeting in RMS.

cancer biology↗

bioRxiv2025

TAK1 is a key regulator of oncogenic signaling and differentiation blockade in rhabdomyosarcoma

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 {beta}-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.

cancer biology↗

bioRxiv2025

Fiber-type vulnerability and proteostasis reprogramming in skeletal muscle during pancreatic cancer cachexia

Cachexia is a debilitating syndrome marked by progressive skeletal muscle wasting, commonly affecting cancer patients, particularly those with pancreatic cancer. Despite its clinical significance, the molecular mechanisms underlying cancer cachexia remain poorly understood. In this study, we utilized single-nucleus RNA sequencing (snRNA-seq) and bulk RNA-seq, complemented by biochemical and histological analyses, to investigate molecular alterations in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Our findings demonstrate that KPC tumor growth induces myofiber-specific changes in the expression of genes involved in proteolytic pathways, mitochondrial biogenesis, and angiogenesis. Notably, tumor progression enhances the activity of specific transcription factors that regulate the mTORC1 signaling pathway, along with genes involved in translational initiation and ribosome biogenesis. Skeletal muscle-specific, inducible inhibition of mTORC1 activity further exacerbates muscle loss in tumor-bearing mice, highlighting its protective role in maintaining muscle mass. Additionally, we uncovered novel intercellular signaling networks within the skeletal muscle microenvironment during pancreatic cancer-induced cachexia. Together, these results reveal previously unrecognized molecular mechanisms that regulate skeletal muscle homeostasis and identify potential therapeutic targets for the treatment of pancreatic cancer-associated cachexia.

cell biology↗

bioRxiv2025

Targeting the canonical ER stress IRE1α/XBP1 pathway counteracts pancreatic cancer-induced skeletal muscle wasting

Cancer-driven cachexia is a deleterious syndrome which involves progressive loss of skeletal muscle mass with or without fat loss, fatigue, and weakness that cannot be reversed by nutritional intake. Recent studies have shown deregulation of endoplasmic reticulum (ER)-induced unfolded protein response (UPR) pathways in skeletal muscle in various catabolic conditions, including cancer growth. However, the role of individual arms of the UPR in the regulation of muscle mass remains poorly understood. Here, we demonstrate that the IRE1/XBP1 arm of the UPR stimulates the activation of ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Furthermore, our results show that IRE1/XBP1 pathway is a key contributor to cachexia as targeted ablation of XBP1 transcription factor in mouse skeletal muscle inhibits KPC tumor-induced muscle wasting. Transcriptionally active XBP1 protein binds to the promoter region of multiple genes, such as Map1lc3b, Fbxo32, and Il6, whose products are involved in skeletal muscle wasting. Treatment of KPC tumor-bearing mice with 4{micro}8C, a small molecule IRE1 inhibitor, reverses cachexia-induced molecular changes and improves skeletal muscle mass and strength. Altogether, our study highlights that the IRE1/XBP1 signaling axis mediates pancreatic cancer-induced muscle wasting and inhibition of this pathway could be a potential approach to mitigate muscle wasting in pancreatic cancer patients.

physiology↗

bioRxiv2025

Hyperactivation of TAK1 causes skeletal muscle pathology reminiscent of inflammatory myopathies

Loss of skeletal muscle mass and strength is a debilitating consequence of various chronic diseases, inflammatory myopathies, and neuromuscular disorders. Inflammation plays a major role in the perpetuation of myopathy in degenerative muscle diseases. TAK1 is a major signaling protein that mediates the activation of multiple signaling pathways in response to inflammatory cytokines and microbial products. Recent studies have demonstrated that TAK1 is essential for the growth and maintenance of skeletal muscle mass in adult mice. However, the effects of overstimulation of TAK1 activity in the regulation of skeletal muscle mass remain unknown. In the present study, using AAV vectors, we investigated the effect of varying levels of TAK1 activation on skeletal muscle in adult mice. Our results demonstrate that while low levels of TAK1 activation improve skeletal muscle mass, sustained hyperactivation of TAK1 causes myopathy in adult mice. Excessive stimulation of TAK1 manifests pathological features, such as myofiber degeneration and regeneration, cellular infiltration, increased expression of proinflammatory molecules, and interstitial fibrosis. Hyperactivation of TAK1 also upregulates proteolytic systems and various catabolic signaling pathways in skeletal muscle of adult mice. Altogether, our study demonstrates that physiological levels of activation of TAK1 lead to myofiber hypertrophy, whereas its hyperactivation results in myofiber damage and other pathological features resembling inflammatory myopathies.

cell biology↗

bioRxiv2024

The TWEAK/Fn14 signaling promotes skeletal muscle wasting during cancer cachexia

Cachexia is an involuntary loss of body weight mostly due to skeletal muscle wasting. The proinflammatory cytokine TWEAK and its receptor Fn14 constitute a major signaling system that regulates skeletal muscle mass in diverse conditions. However, the role of TWEAK/Fn14 system in the regulation of skeletal muscle mass during cancer-induced cachexia remains poorly understood. In this study, we demonstrate that the levels of Fn14, but not TWEAK, are induced in skeletal muscle of multiple mouse models of cancer cachexia. Targeted deletion of Fn14 inhibits muscle wasting and gene expression of multiple components of the ER stress-induced unfolded protein response (UPR) in the KPC mouse model of pancreatic ductal adenocarcinoma (PDAC) cancer cachexia. The TWEAK/Fn14 signaling activates PERK and IRE1 arm of the UPR and inhibits protein synthesis in cultured primary myotubes. Inhibition of PERK using pharmacological or molecular approaches improves protein synthesis and inhibits atrophy in TWEAK-treated cultured myotubes. Silencing of Fn14 in KPC cells prior to their inoculation in pancreas of mice also attenuates tumor growth without having any significant effect on muscle atrophy. The knockdown of Fn14 inhibits proliferation, migration, and invasion of cultured KPC cells. Finally, our results demonstrate that targeted ablation of Fn14 also attenuates muscle atrophy in the Lewis lung carcinoma model of cancer cachexia. Altogether, our study provides initial evidence that the inhibition of TWEAK/Fn14 signaling can prevent tumor growth and skeletal muscle wasting during cancer-induced cachexia.

cell biology↗

bioRxiv2024

Single-nucleus transcriptomic analysis reveals the regulatory circuitry of myofiber XBP1 during regenerative myogenesis

Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) are activated in skeletal muscle in multiple conditions. However, the role of the UPR in the regulation of muscle regeneration remains less understood. We demonstrate that gene expression of various markers of the UPR is induced in both myogenic and non-myogenic cells in regenerating muscle. Genetic ablation of XBP1, a downstream target of the IRE1 arm of the UPR, in myofibers attenuates muscle regeneration in adult mice. Single nucleus RNA sequencing (snRNA-seq) analysis showed that deletion of XBP1 in myofibers perturbs proteolytic systems and mitochondrial function in myogenic cells. Trajectory analysis of snRNA-seq dataset showed that XBP1 regulates the abundance of satellite cells and the formation of new myofibers in regenerating muscle. In addition, ablation of XBP1 disrupts the composition of non-myogenic cells in injured muscle microenvironment. Collectively, our study suggests that myofiber XBP1 regulates muscle regeneration through both cell-autonomous and -non-autonomous mechanisms. HIGHLIGHTSO_LIThe UPR is activated in different cell types during muscle regeneration. C_LIO_LITargeted deletion of XBP1 impairs muscle regeneration in adult mice C_LIO_LIMyofiber XBP1 regulates satellite cell dynamics during regenerative myogenesis C_LIO_LIMyofiber XBP1 regulates abundance of non-myogenic cells in regenerating muscle C_LI

cell biology↗

bioRxiv2022

Temporal regulation of TAK1 to counteract muscular dystrophy

Muscular dystrophy is a group of genetic neuromuscular disorders that involves severe muscle wasting. Transforming growth factor {beta}-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. TAK1 has been recently found to promote myofiber growth in skeletal muscle of adult mice. However, the role of TAK1 in muscle disorders remains poorly understood. In the present study, we have investigated how TAK1 affects progression of dystrophic phenotype in the mdx mouse model of Duchnne muscular dystrophy (DMD). TAK1 is highly activated during peak necrotic phase in mdx mice. Targeted inducible inactivation of TAK1 inhibits muscle injury, necroptosis, and accumulation of macrophages in dystrophic muscle of mdx mice. Additionally, targeted inactivation of TAK1 leads to the activation of autophagy and Notch and Wnt signaling in the dystrophic muscle. However, inactivation of TAK1 significantly reduces myofiber size and muscle contractile function in both young and adult mdx mice. Forced activation of TAK1 in skeletal muscle after peak necrotic phase induces myofiber growth and improves muscle histopathology in mdx mice. Our results suggest that targeted activation of TAK1 can ameliorate disease progression and improve muscle growth in DMD. One Sentence SummaryOur results demonstrate that duly regulation of TAK1 activity ameliorates dystrophic phenotype in a mouse model of Duchnne Muscular Dystrophy.

physiology↗

bioRxiv2021

IRE1/XBP1 signaling promotes skeletal muscle regeneration through a cell non-autonomous mechanism

Skeletal muscle regeneration is regulated by coordinated activation of multiple signaling pathways activated in both injured myofibers and satellite cells. The unfolded protein response (UPR) is a major mechanism that detects and alleviates protein-folding stresses in ER. However, the role of individual arms of the UPR in skeletal muscle regeneration remains less understood. In the present study, we demonstrate that IRE1 (also known as ERN1) and its downstream target, XBP1, are activated in skeletal muscle of mice upon injury. Myofiber-specific ablation of IRE1 or XBP1 in mice diminishes skeletal muscle regeneration that is accompanied with reduced number of satellite cells and their fusion to injured myofibers. Ex vivo cultures of myofiber explants demonstrate that ablation of IRE1 reduces the proliferative capacity of myofiber- associated satellite cells. Myofiber-specific deletion of IRE1 dampens Notch signaling and canonical NF-{kappa}B pathway in skeletal muscle of mice. Our results also demonstrate that targeted ablation of IRE1 reduces skeletal muscle regeneration in the mdx mice, a model of Duchenne muscular dystrophy. Collectively, our results reveal that the IRE1-mediated signaling promotes muscle regeneration through augmenting the proliferation of satellite cells in a cell non- autonomous manner.

cell biology↗