Biology subjects

Pin, F.

Publications and source records attributed to Pin, F..

4 recordsLinked to original sources

bioRxiv2026

Chemotherapy induces tissue NAD+ loss, and downregulation of NAD+ biosynthetic enzyme Nrk2 marks muscle wasting

BackgroundAberrant NAD+ metabolism has been implicated in the pathogenesis of cancer cachexia, highlighting this pathway as a potential therapeutic target to mitigate skeletal muscle wasting. However, it remains unclear whether chemotherapeutic agents contribute to the onset of cachexia by disrupting NAD+ metabolism. Here, we investigated the effects of commonly used chemotherapy regimens on NAD+ metabolism in skeletal muscle and liver of healthy mice. MethodsHealthy mice were treated with either 2-week regimens of folfiri or cisplatin, or 5-week regimens of folfiri or folfox, with vehicle-treated mice serving as controls. Cachexia-related outcomes were assessed, while skeletal muscle and liver tissues were analyzed for NAD metabolites and markers of NAD+ metabolism. Given the consistent downregulation of the NAD+ biosynthetic enzyme Nrk2 in cachectic chemotherapy-treated mice, we examined skeletal muscle Nrk2/NRK2 expression across published murine and human cachexia datasets, and in additional models of muscle wasting and hypertrophy. ResultsNAD+ loss was observed in atrophic muscle following administration of cisplatin (2-week treatment; -14% vs controls, p=0.047) and folfiri (5-week treatment; -18%, p=0.069). In contrast, muscle NAD+ levels were preserved in non-atrophic groups (2-week folfiri and 5-week folfox). Muscle Nrk2 was the most responsive NAD+ biosynthetic enzyme, showing consistent downregulation across chemotherapy models with ongoing or developing muscle loss: cisplatin (-93%, p<0.001), folfiri (-84%, p<0.001) and folfox (-92%, p<0.001). In the liver, NAD+ levels declined after prolonged 5-week folfiri (-20%, p=0.013) and folfox (-15%, p=0.043) treatments. These changes were accompanied by distinct alterations in NAD+ biosynthesis pathways, indicating treatment-specific reorganization of hepatic NAD+ metabolism. Cross-study analyses revealed early and consistent skeletal muscle Nrk2 downregulation across multiple murine cachexia models and human inactivity studies, whereas cachexia-targeted interventions in rodents and resistance training in humans increased its expression. ConclusionsThese findings demonstrate that chemotherapy distrupts tissue NAD+ metabolism, with skeletal muscle NAD+ loss accompanying muscle atrophy and hepatic NAD+ levels declining after prolonged treatment. The early and robust responsiveness of muscle Nrk2 expression to changes in muscle mass underscores its potential as a dynamic indicator for predicting treatment-induced changes in muscle mass. Together, these results provide new molecular insight into the metabolic basis of chemotherapy-induced muscle wasting and support further investigation of NAD+-targeted strategies in this context.

biochemistry↗

bioRxiv2025

GL261 glioblastoma induces delayed body weight gain and stunted skeletal muscle growth in young mice

IntroductionThe survival rate for children and adolescents has increased to over 85%. However, there is limited understanding of the impact of pediatric cancers on muscle development and physiology. Given that brain tumors alone account for 26% of all pediatric cancers, this study aimed to investigate the skeletal muscle consequences of tumor growth in young mice. MethodsC2C12 myotubes were co-cultured with GL261 murine glioblastoma cells to assess myotube size. GL261 cells were then injected subcutaneously into 4-week-old male C57BL/6J mice. Animals were euthanized 28 days post-GL261 implantation. Muscle function was tested in vivo and ex vivo. Muscle protein synthesis was measured via the SUnSET method, and gene/protein expression levels were assessed via Western blotting and qPCR. ResultsIn vitro, the C2C12 cultures exposed to GL261 exhibited myotube atrophy, consistent with a disrupted anabolic/catabolic balance. In vivo, carcass, heart, and fat mass were significantly reduced in the tumor-bearing mice. Skeletal muscle growth was impeded in the GL261 hosts, along with smaller muscle CSA. Both in vivo muscle torque and the ex vivo EDL muscle force were unchanged. At molecular level, the tumor hosts displayed reduced muscle protein synthesis and increased muscle protein ubiquitination, in disagreement with decreased muscle ubiquitin ligase mRNA expression. ConclusionsOverall, we showed that GL261 tumors impact the growth of pediatric mice by stunting skeletal muscle development, decreasing muscle mass, reducing muscle fiber size, diminishing muscle protein synthesis, and altering protein catabolism signaling.

cancer biology↗

bioRxiv2023

Deletion of FNDC5/Irisin modifies murine osteocyte function in a sex-specific manner

Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (KO), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet. Male KO mice have more but weaker bone compared to WT males, and when challenged with a low-calcium diet lost more bone than WT males. To begin to understand responsible molecular mechanisms, osteocyte transcriptomics was performed. Osteocytes from WT females had greater expression of genes associated with osteocytic osteolysis and osteoclastic bone resorption compared to WT males which had greater expression of genes associated with steroid and fatty acid metabolism. Few differences were observed between female KO and WT osteocytes, but with a low calcium diet, the KO females had lower expression of genes responsible for osteocytic osteolysis and osteoclastic resorption than the WT females. Male KO osteocytes had lower expression of genes associated with steroid and fatty acid metabolism, but higher expression of genes associated with bone resorption compared to male WT. In conclusion, irisin plays a critical role in the development of the male but not the female skeleton and protects male but not female bone from calcium deficiency. We propose irisin ensures the survival of offspring by targeting the osteocyte to provide calcium in lactating females, a novel function for this myokine.

physiology↗

bioRxiv2021

PGC-1α in the myofibers regulates the balance between myogenic and adipogenic progenitors affecting muscle regeneration

Skeletal muscle repair is accomplished by satellite cells (MuSC) in cooperation with interstitial stromal cells (ISCs). So far, the relationship between the function of these cells and the metabolic state of myofibers remains unclear. The present study reports alterations in the proportion of both MuSCs and adipogenesis regulators (Aregs) induced by overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1) in the myofibers (MCK-PGC-1 mice). Although PGC-1-driven increase of MuSCs does not accelerate muscle regeneration, myogenic progenitors isolated from MCK-PGC-1 mice and transplanted into intact and regenerating muscles are more prone to fuse with recipient myofibers than those derived from WT donors. Moreover, both young and aged MCK-PGC-1 animals show reduced perilipin-positive areas when challenged with an adipogenic stimulus, demonstrating low propensity to accumulate adipocytes within the muscle. These results provide new insights on the role played by PGC-1 in promoting myogenesis and hindering adipogenesis in the skeletal muscle.

molecular biology↗