Biology subjects

Hulmi, J. J.

Publications and source records attributed to Hulmi, J. J..

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↗

bioRxiv2024

Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training

Investigating repeated resistance training separated by a training break enables exploration of the potential for a proteomic memory of resistance training (RT)-induced skeletal muscle growth. Our aim was to examine skeletal muscle proteome response to 10-week RT (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Thirty healthy, untrained participants conducted either periodic RT (RT1-DT-RT2, n=17) or a 10-week no-training control period (n=13) followed by 20 weeks of RT (n=11). RT included twice-weekly supervised whole-body RT sessions, and resting vastus lateralis biopsies were obtained every ten weeks for proteomics analysis using high-end DIA-PASEFs mass spectrometry. The first RT period altered 150 proteins (93% increased) involved in e.g. energy metabolism and protein processing compared with minor changes during the no-training control period. The proteome adaptations were similar after the second RT compared to baseline demonstrating reproducibility in proteome adaptations to RT. Many of the proteins induced by RT1 were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Interestingly, several proteins increased after RT1 remain elevated after detraining, including carbonyl reductase 1 (CBR1) and proteins involved in muscle contraction, cytoskeleton and calcium-binding. Amongst the latter, calcium-activated protease calpain-2 (CAPN2) has been recently identified as an epigenetic muscle memory gene. We show that resistance training evokes retained protein levels even after 2.5 months of no training. This is the first study to demonstrate a potential proteomic memory of resistance training-induced muscle growth in human skeletal muscle. Key pointsO_LIRepeated resistance training in humans separated by a training break (i.e. detraining) enables the identification of temporal protein signatures over the training, detraining, and retraining periods as well as studying reproducibility of protein changes to resistance training. C_LIO_LIMuscle proteome adaptations were similar after a second period of resistance training when compared to baseline, demonstrating reproducibility in proteome adaptations to earlier resistance training. C_LIO_LIMany of the proteins induced by resistance training were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. C_LIO_LISeveral proteins increased after resistance training remain elevated after detraining, including carbonyl reductase 1 (CBR1) and calcium-binding proteins such as calpain-2 (CAPN2), a recently identified epigenetic muscle memory gene. C_LIO_LIHuman skeletal muscle experiences retained protein changes following resistance training persisting over two months demonstrating a potential proteomic memory of resistance training-induced muscle growth. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/624068v3_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1f0ae2corg.highwire.dtl.DTLVardef@3af3b4org.highwire.dtl.DTLVardef@55d064org.highwire.dtl.DTLVardef@1e46bf9_HPS_FORMAT_FIGEXP M_FIG Human skeletal muscle proteome response was investigated after 10-week resistance training (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Many of the proteins were reversed towards baseline after DT and increased again after RT2. These reversible proteins were especially involved in aerobic energy metabolism. However, several RT-induced proteins remain elevated after DT, including carbonyl reductase 1 (CBR1) and many proteins involved in muscle contraction or cytoskeleton and calcium-binding. Amongst the latter, calcium-activated protease calpain-2 (CAPN2) is a recently identified epigenetic muscle memory gene. This study shows that resistance training evokes retained protein levels even after 2.5 months of no training and demonstrates a potential proteomic memory of RT-induced muscle growth in human skeletal muscle. Created in BioRender.com. C_FIG

physiology↗

bioRxiv2022

Age but not menopausal status is linked to lower resting energy expenditure

ContextIt remains uncertain whether aging before late adulthood and menopause are associated with fat-free mass and fat mass-adjusted resting energy expenditure (REEadj). ObjectivesWe investigated whether REEadj differs between middle-aged and younger women and between middle-aged women with different menopausal statuses. We repeated the age group comparison between middle-aged mothers and their daughters to partially control for genotype. We also explored whether serum estradiol and follicle-stimulating hormone concentrations explain REEadj in midlife. MethodsWe divided 120 women, including 16 mother-daughter pairs, into age groups; group I (n = 26) consisted of participants aged 17-21, group II (n = 35) of those aged 22-38 and group III (n = 59) of those aged 41-58 years. The women in group III were further categorized as pre- or perimenopausal (n = 19), postmenopausal (n = 30) or postmenopausal hormone therapy users (n = 10). REE was assessed using indirect calorimetry, body composition using dual-energy X-ray absorptiometry and hormones using immunoassays. ResultsThe REEadj of group I was 126 kcal/d (95% CI: 93-160) higher than that of group III, and the REEadj of group II was 88 kcal/d (95% CI: 49-127) higher. Furthermore, daughters had a 100 kcal/d (95% CI: 63-138 kcal/d) higher REEadj than their middle-aged mothers (all P < 0.001). In group III, REEadj was not lower in postmenopausal women and did not vary by sex hormone concentrations. ConclusionsWe demonstrated that REEadj declines with age in women before late adulthood, also when controlling partially for genetic background, and that menopause may not contribute to this decline.

physiology↗

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↗