Similar Datasets
Project description:Skeletal muscle wasting is a hallmark of cachexia, a cancer-associated syndrome that severely affects patients’ quality of life. Emerging evidence indicates that at early stages of cachexia a large transcriptional network of genes involved in mitochondrial biogenesis, dynamics, and function is down-regulated in skeletal muscle, thus leading to mitochondrial dysfunction and muscle wasting. Here, by exploiting in vivo and in vitro cachexia models, we report that i) tumor-induced impairment of cAMP/CREB1 signaling in skeletal muscle contributes to the downregulation of the transcriptional network sustaining mitochondrial function; ii) the cAMP-hydrolyzing phosphodiesterases 4D (PDE4D), whose transcript variants are deregulated in cachectic muscle, mediates tumor-induced cAMP signaling impairment in vitro. iii) boosting cAMP signaling by targeting PDE4 in vivo rescues mitochondrial-related gene expression, mitochondrial dysfunction, and mitigates muscle wasting. Collectively, we identified tumor-induced impairment of cAMP/CREB1 signaling as a driver of skeletal muscle mitochondrial dysfunction occurring during cancer cachexia.
2025-09-11 | GSE271830 | GEO
Project description:106 C26 murine adenocarcinoma cells in 100 μl of PBS were subcutaneously injected in the right flank of 2-month-old male Balb/c mice. Starting from day 4 post tumor inoculation, C26-bearing animals were injected intraperitoneally with rolipram (3 mg/kg) or vehicle (1,86% ethanol in saline). RNAseq was performed on gastrocnemius muscle from control (without tumor), C26 vehicle-treated, and rolipram-treated mice.
2025-09-11 | GSE271492 | GEO
Project description:Impaired cAMP/CREB1 signaling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
| PRJNA1133703 | ENA
Project description:Impaired cAMP/CREB1 signaling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia [RNA-seq]
| PRJNA1131818 | ENA
Project description:Impaired cAMP/CREB1 signaling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia [ChIP-seq]
| PRJNA1133712 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber's size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.
| S-EPMC11488855 | biostudies-literature
Project description:Background. Pancreatic Ductal AdenoCarcinoma (PDAC), the most frequent pancreatic cancer, is a deadly cancer since often diagnosed late and resistant to current therapies. A high proportion of PDAC patients are affected by cachexia induced by the tumor. This cachexia, characterized by loss of muscle mass and strength, contributes to patient frailty and poor therapeutic response. We showed that mitochondrial metabolism is reprogrammed in PDAC tumor cell and constitutes a vulnerability, opening novel therapeutic avenues. The objective of the present work was to investigate the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Methods. Our study focused on the gastrocnemius muscle of genetically-engineered mice developing spontaneously a PDAC associated with cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-10 weeks to control littermates. We did an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and western blotting analyses. Results. The cachectic KIC PDAC mice show a severe sarcopenia with loss of muscle mass and strength associated with a diminution in muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophic muscles show decreased respiratory capacities and structural alterations (“hyperfused” mitochondria), associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways at the molecular level. Increased expression of multiple reactive oxygen species (ROS) defense genes suggests oxidative stress prone to affect mitochondrial macromolecules and homeostasis. Interestingly, multiple genes and proteins involved in DNA metabolism pathways, such as DNA damage, degradation of DNA, nucleotide synthesis, and folate pathway were found altered in sarcopenic mitochondria. While the number of mitochondria was not changed, the mitochondrial mass was decreased by a factor of 2 and the mitochondrial DNA by a factor of 3, suggesting a defect in mitochondrial genome homeostasis. Conclusions. We unveiled that mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein, but concern also lipids, ROS and nucleic acids. Our data provide a frame to guide towards the most relevant molecular markers that would be affected at the start of tumor development and could be targets in the clinic to limit PDAC-induced cachexia at early stages of the pathology.
2024-04-09 | PXD036752 | Pride
Project description:Pancreatic Ductal AdenoCarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer since it is often diagnosed late and resistant to current therapies. A large proportion of PDAC patients are affected by tumor-induced cachexia. This cachexia, characterized by a loss of muscle mass and strength (sarcopenia), contributes to patient frailty and poor therapeutic response. We have shown that mitochondrial metabolism is reprogrammed in PDAC tumors and constitutes a vulnerability, opening new therapeutic avenues. The objective of this work was to study the molecular mechanisms underlying mitochondrial remodeling in PDAC cachectic skeletal muscle. Our study focused on the gastrocnemius muscle of genetically-engineered mice spontaneously developing an autochthonous pancreatic tumor and cachexia (KIC GEMM). We compared KIC mice developing a pancreatic tumor in 9-11 weeks to control littermates. We performed an integrative study combining in vivo functional analyses by non-invasive Magnetic Resonance, and ex-vivo histology, Seahorse, RNA-sequencing, and proteomic mass spectrometry and Western blotting analyses. KIC cachectic PDAC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber’s size and induction of protein degradation processes. Mitochondrial alterations in skeletal muscle play a central role in PDAC-induced cachexia. Muscle atrophy is associated with strong mitochondrial metabolic defects that are not limited to carbohydrates and protein metabolism, but concern also lipids, ROS and nucleic acids. Our data provide a framework to guide towards the most relevant molecular markers that would be affected early in tumor development and could be targeted in the clinic to limit PDAC-induced cachexia at early stages of the pathology.
2024-03-11 | GSE226898 | GEO
Project description:Chemerin is a novel adipocyte-derived factor that induces insulin resistance in skeletal muscle. However, the effect of chemerin on skeletal muscle mitochondrial function has received little attention. In the present study, we investigated whether mitochondrial dysfunction is involved in the pathogenesis of chemerin-mediated insulin resistance. In this study, we used recombinant adenovirus to express murine chemerin in C57BL/6 mice. The mitochondrial function and structure were evaluated in isolated soleus muscles from mice. The oxidative mechanism of mitochondrial dysfunction in cultured C2C12 myotubes exposed to recombinant chemerin was analysed by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction. The overexpression of chemerin in mice reduced the muscle mitochondrial content and increased mitochondrial autophagy, as determined by the increased conversion of LC3-I to LC3-II and higher expression levels of Beclin1 and autophagy-related protein-5 and 7. The chemerin treatment of C2C12 myotubes increased the generation of mitochondrial reactive oxygen species, concomitant with a reduced mitochondrial membrane potential and increased the occurrence of mitochondrial protein carbonyls and mitochondrial DNA deletions. Knockdown of the expression of chemokine-like receptor 1 or the use of mitochondria-targeting antioxidant Mito-TEMPO restored the mitochondrial dysfunction induced by chemerin. Furthermore, chemerin exposure in C2C12 myotubes not only reduced the insulin-stimulated phosphorylation of protein kinase B (AKT) but also dephosphorylated forkhead box O3α (FoxO3α). Chemerin-induced mitochondrial autophagy likely through an AKT-FoxO3α-dependent signalling pathway. These findings provide direct evidence that chemerin may play an important role in regulating mitochondrial remodelling and function in skeletal muscle.
| S-EPMC4420601 | biostudies-literature
Project description:BackgroundSkeletal muscle is sensitive to bile acids (BA) because it expresses the TGR5 receptor for BA. Cholic (CA) and deoxycholic (DCA) acids induce a sarcopenia-like phenotype through TGR5-dependent mechanisms. Besides, a mouse model of cholestasis-induced sarcopenia was characterised by increased levels of serum BA and muscle weakness, alterations that are dependent on TGR5 expression. Mitochondrial alterations, such as decreased mitochondrial potential and oxygen consumption rate (OCR), increased mitochondrial reactive oxygen species (mtROS) and unbalanced biogenesis and mitophagy, have not been studied in BA-induced sarcopenia.MethodsWe evaluated the effects of DCA and CA on mitochondrial alterations in C2C12 myotubes and a mouse model of cholestasis-induced sarcopenia. We measured mitochondrial mass by TOM20 levels and mitochondrial DNA; ultrastructural alterations by transmission electronic microscopy; mitochondrial biogenesis by PGC-1α plasmid reporter activity and protein levels by western blot analysis; mitophagy by the co-localisation of the MitoTracker and LysoTracker fluorescent probes; mitochondrial potential by detecting the TMRE probe signal; protein levels of OXPHOS complexes and LC3B by western blot analysis; OCR by Seahorse measures; and mtROS by MitoSOX probe signals.ResultsDCA and CA caused a reduction in mitochondrial mass and decreased mitochondrial biogenesis. Interestingly, DCA and CA increased LC3II/LC3I ratio and decreased autophagic flux concordant with raised mitophagosome-like structures. In addition, DCA and CA decreased mitochondrial potential and reduced protein levels in OXPHOS complexes I and II. The results also demonstrated that DCA and CA decreased basal, ATP-linked, FCCP-induced maximal respiration and spare OCR. DCA and CA also reduced the number of cristae. In addition, DCA and CA increased the mtROS. In mice with cholestasis-induced sarcopenia, TOM20, OXPHOS complexes I, II and III, and OCR were diminished. Interestingly, the OCR and OXPHOS complexes were correlated with muscle strength and bile acid levels.ConclusionOur results showed that DCA and CA decreased mitochondrial mass, possibly by reducing mitochondrial biogenesis, which affects mitochondrial function, thereby altering potential OCR and mtROS generation. Some mitochondrial alterations were also observed in a mouse model of cholestasis-induced sarcopenia characterised by increased levels of BA, such as DCA and CA.
| S-EPMC10249330 | biostudies-literature