Biology subjects

Penna, F.

Publications and source records attributed to Penna, 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

Fasting-mimicking diet counteracts gut microbial dysbiosis in experimental Lynch syndrome

The development of colorectal cancer (CRC) is largely influenced by hereditary factors, with up to one-third of cases linked to genetic predisposition. In parallel, environmental factors such as diet and intestinal microbiota play a significant role. Lynch syndrome (LS), the most common form of hereditary CRC, is due to mutations in DNA mismatch repair genes. Diet interventions such as calorie restriction (CR) can modify the course of the disease, altering nutrient supply and promoting beneficial microbial populations. Fasting-mimicking diets (FMD) are plant-based CR regimens that showed promise in modulating the gut microbiota and suppressing CRC progression in pre-clinical ectopic cancer models. In this study, Villin-Cre/Msh2-floxed (VCM) mice, modelling LS, were subjected to periodic FMD cycles for 10 months. Although not impacting on macroscopic tumor development, FMD influenced animal weight in a sexually dimorphic manner. Moreover, shotgun metagenomic sequencing revealed that FMD mitigated the dysbiotic longitudinal changes associated with cancer onset, preserving beneficial species, such as Lactobacillus johnsonii, and reducing adverse species, such as Escherichia coli. Metabolic pathway analysis also showed significant differences, with FMD preventing the upregulation of pathways involved in amino acid and nucleotide synthesis, potentially promoting tumor growth. Overall, the findings suggest that periodic FMD may be adopted as an adjuvant therapy in LS management, counteracting gut microbiota alterations.

pathology↗

bioRxiv2022

NAD+ repletion with niacin counteracts cancer cachexia

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirmed that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of different mouse models and cachectic cancer patients. Testing NAD+ repletion therapy in cachectic mice revealed that NAD+ precursor, vitamin B3 niacin, efficiently corrected tissue NAD+ levels, improved mitochondrial metabolism and ameliorated cancer- and chemotherapy-induced cachexia. To examine NAD+ metabolism in a clinical setting, we showed that the low expression of NRK2 in cancer patients correlated with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose a novel therapy target, NAD+ metabolism, for cachectic cancer patients.

molecular biology↗

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↗