Biology subjects

Fajardo, V.

Publications and source records attributed to Fajardo, V..

8 recordsLinked to original sources

bioRxiv2024

Housing temperature dictates the systemic and tissue specific molecular responses to cancer in mice

Cancer cachexia is a metabolic condition affecting up to 80% of patients with cancer. Cachexia is mediated by reduced muscle and fat mass and impaired function, and it lowers survival for patients. With no approved drugs to treat cachexia, preclinical efforts focus on understanding the molecular mechanisms underlying this condition to reveal treatment targets. Housing laboratory mice at ambient temperature imposes cold stress, leading to induced thermogenic activity and consequent whole-body metabolic adaptations. Yet, the impact of housing temperature in in vivo preclinical cachexia remains unknown. We found that thermoneutral (TN) housing in C26 carcinoma-bearing (C26) mice affected lean and fat mass, but not muscle weight or force. TN housing improved glucose tolerance in C26 mice, while enhancing circulating abundance of FGF21 and IL-6. Thermogenic tissues, especially brown adipose tissue, exhibited housing temperature-dependent molecular responses to cancer in oxygen consumption, ATP levels and SERCA ATPase activity, which are all crucial for cancer-induced whole-body metabolic adaptations. We conclude that molecular and systemic adaptations to cancer in mice critically depend on housing temperature, which should be considered in the design and interpretation of preclinical cancer studies.

physiology↗

bioRxiv2024

Spaceflight increases sarcoplasmic reticulum Ca2+ leak and this cannot be counteracted with BuOE treatment

Spending time in a microgravity environment is known to cause significant skeletal muscle atrophy and weakness via muscle unloading, which can be partly attributed to Ca2+ dysregulation. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is responsible for bringing Ca2+ from the cytosol into its storage site, the sarcoplasmic reticulum (SR), at the expense of ATP. We have recently demonstrated that, in the soleus of spaceflown mice, the Ca2+ uptake ability of the SERCA pump is severely impaired and this may be attributed to increases in reactive oxygen/nitrogen species (RONS), to which SERCA is highly susceptible. The purpose of this study was therefore to investigate whether treatment with the antioxidant, MnTnBuOE-2-PyP (BuOE), could attenuate muscle atrophy and SERCA dysfunction. We received soleus muscles from the rodent research 18 mission which had male mice housed on the international space station for 35 days and treated with either saline or BuOE. Spaceflight significantly reduced the soleus:body mass ratio and significantly increased SERCAs ionophore ratio, a measure of SR Ca2+ leak, and 4-HNE content (marker of RONS), none of which could be rescued by BuOE treatment. In conclusion, we find that spaceflight induces significant soleus muscle atrophy and SR Ca2+ leak that cannot be counteracted with antioxidant treatment. Future work should investigate alternative therapeutics that are specifically aimed at increasing SERCA activation or reducing Ca2+ leak. HighlightsO_LISpaceflight induces soleus muscle atrophy and increases SR Ca2+ leak C_LIO_LITreatment with the antioxidant, BuOE, was unable to attenuate the detrimental effects of spaceflight on the soleus muscle C_LIO_LIFuture work should investigate the potential benefits of SERCA activation or reducing SR Ca2+ leak C_LI

physiology↗

bioRxiv2023

Loss of neuronatin increases susceptibility of SERCA to thermal inactivation

O_LIPhospholamban and sarcolipin are two key regulators of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) that have been shown to protect SERCA from thermal inactivation in muscle C_LIO_LIWe have recently detected neuronatin (NNAT) in murine skeletal muscle and have shown that it too regulates SERCA C_LIO_LIHere, we questioned whether NNAT would also protect SERCA from thermal inactivation C_LIO_LIIn response to 60 min of heat stress at 40{degrees}C, maximal SERCA activity was significantly reduced in soleus homogenates obtained from NNAT knockout mice (-23%) but not wild-type mice (-5%). C_LIO_LIOur results add further support for NNATs role in regulating SERCA function in murine muscle C_LI

physiology↗

bioRxiv2022

Sclerostin influences exercise-induced adaptations in body composition and white adipose tissue morphology in male mice

Sclerostin is an inhibitor of the osteogenic Wnt/{beta}-catenin signalling pathway that has an endocrine role in regulating adipocyte differentiation and metabolism. Additionally, subcutaneous white adipose tissue (scWAT) sclerostin content decreases following exercise training (EXT). Therefore, we hypothesized that EXT-induced reductions in adipose tissue sclerostin may play a role in regulating adaptations in body composition and whole-body metabolism. To test this hypothesis, 10-week-old male C57BL/6J mice were either sedentary (SED) or performing 1h of treadmill running at [~]65-70% VO2max 5 d/week (EXT) for 4 weeks and had subcutaneous (s.c) injections of either saline (C) or recombinant sclerostin (S) (0.1 mg/kg body mass) 5 d/week; thus, making 4 groups (SED-C, EXT-C, SED-S, and EXT-S; n=12/group). No differences in body mass were observed between experimental groups, while food intake was higher in EXT (p=0.03) and S (p=0.08) groups. There was a higher resting energy expenditure in all groups compared to SED-C. EXT-C had a higher lean mass and lower fat mass percentage compared to SED-C and SED-S. No differences in body composition were observed in either the SED-S or EXT-S groups. Lower scWAT (inguinal), vWAT (epididymal) mass, and scWAT adipocyte cell size and increased percentage of multilocular cells in scWAT were observed in the EXT-C group compared to SED-C, while lower vWAT was only observed in the EXT-S group. EXT mice had increased iWAT Lrp4 and mitochondrial content and sclerostin treatment only inhibited increased Lrp4 content with EXT. Together, these results provide evidence that reductions in resting sclerostin with exercise training may influence associated alterations in energy metabolism and body composition, particularly in scWAT.

physiology↗

bioRxiv2022

Tideglusib mitigates dystrophic pathology in skeletal muscle and restores diastolic function in young D2 mdx mice

Introductory paragraphDuchenne muscular dystrophy (DMD) is a severe X-linked muscle wasting disorder that affects 1 in 5,000 males worldwide1. It is caused by the absence of functional dystrophin, which compromises muscle integrity, leading to progressive muscle wasting and weakness2. Glucocorticoids are the standard of care for patients with DMD as they delay the loss of ambulation by an average of 3 years3; however, they are also associated with adverse effects such as insulin resistance and increased risk of type 2 diabetes4. Thus, alternative therapeutic options should be explored. Here, we show that treating the DBA/2J mdx mouse with the glycogen synthase kinase 3 (GSK3) inhibitor, tideglusib, improved skeletal muscle function and insulin sensitivity, while also attenuating the hypermetabolic phenotype previously observed in these mice5. Furthermore, treating mdx mice with the GSK3 inhibitor, lithium, augmented the benefits of voluntary wheel running on insulin sensitivity and skeletal muscle function despite running half of the total distance compared to control-treated mdx mice. This is important given that some patients with DMD may not be able to engage in adequate amounts of physical activity. Thus, GSK3 inhibition alone or in combination with exercise can enhance skeletal muscle function and insulin sensitivity in mdx mice.

physiology↗

bioRxiv2021

SERCA-mediated calcium uptake in the DBA/2J vs C57BL/10 mdx models of Duchenne muscular dystrophy

The DBA/2J (D2) mdx mouse has emerged as a more severe model of Duchenne muscular dystrophy when compared to the traditional C57BL/10 (C57) mdx mouse. Here, we questioned whether sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) function would differ in muscles from young D2 and C57 mdx mice. In gastrocnemius muscles, both D2- and C57 mdx mice exhibited signs of impaired Ca2+ uptake, however, this was more severe in D2 mdx mice. Maximal SERCA activity was lowered only in D2 mdx gastrocnemius muscles and not C57 mdx muscles. Furthermore, in the left ventricle and diaphragm, Ca2+ uptake was impaired in C57 mdx muscles with lowered rates of Ca2+ uptake compared with C57 WT mice, whereas in muscles from D2 mdx mice, rates of Ca2+ uptake were unattainable due to the severe impairments in their ability to transport Ca2+. Overall, our study demonstrates that SERCA function is drastically impaired in young D2 mdx mice.

pathology↗

bioRxiv2020

Single-cell transcriptomic analysis of SARS-CoV-2 reactive CD4+ T cells

The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4+ T cells from 32 COVID-19 patients. In patients with severe disease compared to mild disease, we found increased proportions of cytotoxic follicular helper (TFH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2 reactive regulatory T cells. Importantly, the CD4-CTLs were highly enriched for the expression of transcripts encoding chemokines that are involved in the recruitment of myeloid cells and dendritic cells to the sites of viral infection. Polyfunctional T helper (TH)1 cells and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide so far unprecedented insights into the gene expression patterns of SARS-CoV-2 reactive CD4+ T cells in distinct disease severities.

immunology↗

bioRxiv2018

Limits to a classic paradigm: Most transcription factors regulate genes in multiple biological processes

Transcription factors (TFs) are important drivers of cellular decision-making. When bacteria encounter a change in the environment, transcription factors alter the expression of a defined set of genes in order to adequately respond. It is commonly assumed that genes regulated by the same TF should be involved in the same biological process. Examples of this are methods that rely on coregulation to infer function of not yet annotated genes. We have previously shown that only 21% of TFs regulate functionally homogeneous genes based on the proximity of their catalyzed reactions in the metabolic network. Here, we provide more evidence to support the claim that a one TF/one process relationship is not a general property. We show that the observed functional heterogeneity of regulons is not a result of the quality of the annotation of regulatory interactions, or the absence of protein-metabolite interactions, and is also present when function is defined by Gene Ontology terms. Furthermore, the observed functional heterogeneity is different from the one expected by chance, supporting the notion that it is a biological property. To further explore the relationship between transcriptional regulation and metabolism, we analyze 5 other types of regulatory groups and identify complex regulons (i.e. genes regulated by the same combination of TFs) as the most functionally homogeneous, which is supported by coexpression data. Whether higher levels of related functions exist beyond metabolism and current functional annotations, remains an open question.

bioinformatics↗