bims-musmir 2025-01-19 papers

BMC Genomics. 2025 Jan 13. 26(1): 29

Unravelling the transcriptomic symphony of muscle ageing: key pathways and hub genes altered by ageing and caloric restriction in rat muscle revealed by RNA sequencing.

Gulam Altab, Brian J Merry, Charles W Beckett, Priyanka Raina, Inês Lopes, Katarzyna Goljanek-Whysall, João Pedro de Magalhães.

Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlights gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.

Keywords: Diet; Functional genomics; Nutrigenomics; Sarcopenia

DOI: https://doi.org/10.1186/s12864-024-11051-1

J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13668

Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer.

Daria Neyroud, Andrew C D'Lugos, Enrique J Trevino, Chandler S Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R Deyhle, Justina Brantley, Lam Le, Andrew R Judge, Sarah M Judge.

BACKGROUND: Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.
METHODS: To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild-moderate cachexia (D12 and D14) and advanced cachexia (endpoint).
RESULTS: During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8-endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ+ fibroadipogenic progenitors (+2.5 to +3.8-fold; D10-endpoint vs. Sham, p < 0.05), fibre atrophy (-16% to -24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8-fold; D14-endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (-55%, p = 0.0074) and diaphragm excursion (-43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.
CONCLUSIONS: In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.

Keywords: cancer cachexia; inflammatory response; muscle atrophy; muscle fibrosis; pancreatic cancer

DOI: https://doi.org/10.1002/jcsm.13668

bioRxiv. 2024 Dec 31. pii: 2024.12.30.630679. [Epub ahead of print]

Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.

Natalia M Weinzierl, Jayarani Putri, Kathryn M Spitler, Erin E Talbert.

Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Despite decades of research, therapeutic options for cancer cachexia remain limited. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand mechanisms underlying cachexia. One such model is the Kras LSL-G12D , Ptf1a Cre-ER/+ , Pten flox/flox (KPP) model, which utilizes an inducible Cre recombinase to allow tumor development to be initiated at any age by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 weeks of age. However, mice are still rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 weeks of age (KPP10). Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared to non-tumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that overall survival was significantly shorter in female KPP10 mice compared to KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice.
NEW & NOTEWORTHY: Although male mice experience greater relative body weight losses, similar skeletal muscle and adipose tissue wasting occurs between male and female mice in the Kras LSL-G12D , Ptf1a Cre-ER/+ , Pten flox/flox (KPP) model of pancreatic-cancer induced cachexia. Greater weight loss in males may be related to longer survival. However, differences in tamoxifen dose relative to body weight may have accelerated tumor formation in female mice and therefore may be a relevant consideration for inducible tumor models.

DOI: https://doi.org/10.1101/2024.12.30.630679

Adv Sci (Weinh). 2025 Jan 13. e2410439

Liver-Secreted Extracellular Vesicles Promote Cirrhosis-Associated Skeletal Muscle Injury Through mtDNA-cGAS/STING Axis.

Xiaoli Fan, Yunke Peng, Bo Li, Xiaoze Wang, Yifeng Liu, Yi Shen, Guofeng Liu, Yanyi Zheng, Qiaoyu Deng, Jingping Liu, Li Yang.

Skeletal muscle atrophy (sarcopenia) is a serious complication of liver cirrhosis, and chronic muscle inflammation plays a pivotal role in its pathologenesis. However, the detailed mechanism through which injured liver tissues mediate skeletal muscle inflammatory injury remains elusive. Here, it is reported that injured hepatocytes might secrete mtDNA-enriched extracellular vesicles (EVs) to trigger skeletal muscle inflammation by activating the cGAS-STING pathway. Briefly, injured liver secreted increased amounts of EVs into circulation, which are then engulfed primarily by macrophages in skeletal muscle and subsequently induce cGAS-STING signaling and its-mediated inflammatory response in muscles. In contrast, suppression of hepatic EV secretion or STING signaling significantly alleviated cirrhosis-induced skeletal muscle inflammation and muscle atrophy in vivo. Circulating EVs from cirrhotic patients showed higher levels of mtDNA, and the levels of EV-mtDNA positively correlated with the severity of liver injury. In injured hepatocytes, mitochondrial damage promoted the release of cytosolic mtDNA and the subsequent secretion of mtDNA-enriched EVs. This study reveals that injured hepatocyte-derived EVs induce skeletal muscle inflammation via the mtDNA‒STING axis, while targeted blockade of liver EV secretion or STING signaling represents a potential therapeutic approach for preventing cirrhosis-associated skeletal muscle atrophy.

Keywords: cGAS‐STING; extracellular vesicles; liver fibrosis; mtDNA; skeletal muscle atrophy

DOI: https://doi.org/10.1002/advs.202410439