Cardiac fibrosis contributes to systolic and diastolic dysfunction and can disrupt electrical pathways in the heart. There are currently no therapies that prevent or reverse fibrosis in human cardiac disease. However, animals like freshwater turtles undergo seasonal remodeling of their hearts, demonstrating the plasticity of fibrotic remodeling. In Trachemys scripta, cold temperature affects cardiac load, suppresses metabolism, and triggers a cardiac remodeling response that includes fibrosis.
We investigated this remodeling using Fourier transform infrared (FTIR) imaging spectroscopy, together with functional assessment of muscle stiffness, and molecular, histological, and enzymatic analyses in control (25°C) T. scripta and after 8 weeks of cold (5°C) acclimation.
FTIR revealed an increase in absorption bands characteristic of protein, glycogen, and collagen following cold acclimation, with a corresponding decrease in bands characteristic of lipids and phosphates. Histology confirmed these responses. Functionally, micromechanical stiffness of the ventricle increased following cold exposure assessed via atomic force microscopy (AFM) and was associated with decreased activity of regulatory matrix metalloproteinases (MMPs) and increased expression of MMP inhibitors (TMPs) which regulate collagen deposition.
By defining the structural and metabolic underpinnings of the cold-induced remodeling response in the turtle heart, we show commonalities between metabolic and fibrotic triggers of pathological remodeling in human cardiac disease. We propose the turtle ventricle as a novel model for studying the mechanisms underlying fibrotic and metabolic cardiac remodeling.
The locus coeruleus (LC) is one of the earliest brain regions affected by phosphorylated tau (p-tau) in Alzheimer's disease (AD). Using the P301S mouse model, we investigated the temporal progression of tau pathology and its functional consequences.
Immunohistochemistry was used to assess p-tau deposition in LC noradrenergic neurons at 2–3 and 5–6 months. Electrophysiological recordings evaluated neuronal hyperexcitability, measuring membrane potential, rheobase, and spontaneous action potential (AP) frequency in P301S and wild-type (WT) mice. Fast-scan cyclic voltammetry (FSCV) was used to measure norepinephrine (NE) release. GABA(A) receptor subunit expression was analyzed via immunoblotting.
P-tau was detected in LC neurons as early as 2–3 months, with a rostral-to-caudal gradient, and by 5–6 months, nearly all LC neurons exhibited p-tau immunoreactivity. P301S neurons showed hyperexcitability, characterized by depolarized membrane potentials, a more negative rheobase, and increased spontaneous AP frequency. Synaptic blockade elicited a reduced increase in AP frequency, suggesting diminished inhibitory tone. GABA(A) α2 subunit expression significantly declined with age in P301S mice, whereas α3 remained unchanged. FSCV showed significantly elevated NE release in P301S mice at 3 and 6 months compared to WT.
The findings highlight early LC dysfunction in tauopathies, characterized by increased excitability, reduced inhibitory tone, and exaggerated NE release. This hyperactivity may contribute to excitotoxicity and downstream dysfunction in LC-regulated brain regions. Targeting LC hyperactivity and restoring inhibitory signaling could be promising therapeutic strategies for mitigating AD progression.
Isolated, perfused hearts are viable for hours outside the body, and important research findings have been made using mouse hearts ex vivo. In the Langendorff perfusion mode, the coronary tree is perfused via retrograde flow of a perfusate down the ascending aorta. Although the Langendorff setup is generally simpler and quicker to establish, the working heart mode allows the heart to function in a more physiologically relevant manner, where the perfusate is directed into the left ventricle via the left atrium. The contracting, fluid-filled ventricle will eject the perfusate into the aorta in a more physiologically relevant manner, lifting the physiological relevance of the contractile and energetic data. The workload on the heart (preload, afterload and heart rate) can be precisely adjusted in the working, isolated heart, and the ventricular performance, for example, end-diastolic and end-systolic pressures, stroke volume, cardiac output, and oxygen consumption can be determined. Moreover, using pressure-volume catheters, ventricular performance can be assessed in great detail. With the present review, we highlight the benefits and drawbacks of the technique and indicate where particular attention must be put when building the working heart setup, designing experiments, executing the studies, and analyzing the obtained data.
Mitochondria play key roles in neuronal activity, particularly in modulating agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC), which regulates food intake. FAM163A, a newly identified protein, is suggested to be part of the mitochondrial proteome, though its functions remain largely unknown. This study aimed to investigate the effects of Fam163a knockdown and mitochondrial dysfunction on food intake, AgRP neuron activity, and mitochondrial function in the hypothalamus.
Male C57BL/6 and AgRP-Cre mice received intracranial injections of either Fam163a shRNA, rotenone, or appropriate controls. Behavioral assessments included food intake, locomotor activity, and anxiety-like behaviors. qRT-PCR was used to quantify the expression of the genes related to food intake, mitochondrial biogenesis, dynamics, and oxidative stress. Blood glucose, serum insulin, and leptin levels were measured. Electrophysiological patch-clamp recordings were used to assess the AgRP neuronal activity.
Fam163a knockdown in the ARC increased the cumulative food intake in short term (first 7 days) without altering the 25-day food intake and significantly increased the Pomc mRNA expression. Fam163a silencing significantly reduced leptin levels. Both Fam163a knockdown and rotenone significantly reduced the firing frequency of AgRP neurons. Neither Fam163a silencing nor rotenone altered locomotor or anxiety-like behaviors. Fam163a knockdown and rotenone differentially altered the expression of mitochondrial biogenesis-, mitophagy-, fusion-, and oxidative stress-related genes.
Hypothalamic FAM163A may play a role in modulating AgRP neuronal activity through regulating mitochondrial biogenesis, dynamics, and redox state. These findings provide insights into the role of FAM163A and mitochondrial stress in the central regulation of metabolism.
Aging decreases the metabolic rate and increases the risk of metabolic diseases, highlighting the need for alternative strategies to improve metabolic health. Heat treatment (HT) has shown various metabolic benefits, but its ability to counteract aging-associated metabolic slowdown remains unclear. This study aimed to investigate the impact of whole-body HT on energy metabolism, explore the potential mechanism involving the heat sensor TRPV1, and examine the modulation of gut microbiota.
Ten-month-old female C57BL/6 mice on a high-fat (HF) diet (45% calories from fat) were exposed to daily HT in a 40–41°C heat chamber for 30 min, 5 days a week for 6 weeks. Metabolic changes, including core body temperature and lipid metabolism transcription in adipose tissue and liver, were assessed. Human brown adipocytes were used to confirm metabolic effects in vitro.
HT significantly reduced serum lactate dehydrogenase levels, indicating mitigation of tissue damage. HT attenuated weight gain, improved insulin sensitivity, and increased beta-oxidation in the liver and brown fat. In thermogenic adipose tissue, HT enhanced TRPV1 and Ca2+/ATPase pump expression, suggesting ATP-dependent calcium cycling, which was confirmed in human brown adipocytes. Interestingly, HT also reduced the firmicutes/bacteroides ratio and altered gut microbiota, suppressing HF diet-enriched microbial genera such as Tuzzerella, Defluviitaleaceae_UCG-011, Alistipes, and Enterorhabdus.
HT attenuates aging- and diet-associated metabolic slowdown by increasing futile calcium cycling, enhancing energy expenditure, and altering gut microbiota in middle-aged female C57BL/6 mice. HT may offer a promising strategy to improve metabolic health, especially in aging populations.
Silencing of DEP-domain containing mTOR-interacting protein (DEPTOR), an endogenous inhibitor of the mammalian target of rapamycin (mTOR) pathway, increases mTOR signaling and System A/L amino acid transport activity in cultured primary human trophoblast cells. However, there is no evidence supporting the regulatory role of DEPTOR signaling in placental function in vivo. We hypothesized that trophoblast-specific Deptor knockdown (KD) in mice increases trophoblast mTOR signaling, amino acid transport, and enhances fetal growth.
We generated trophoblast-specific DeptorKD transgenic mice, and at embryonic day 18.5, placentas were analyzed to confirm knockdown efficiency, specificity, and mTOR signaling pathway levels. Trophoblast plasma membrane (TPM) System A/L amino acid transport expression and activity were also determined. We also examined the relationship between birthweight and DEPTOR protein levels in human placentas collected at term from appropriate for gestational age (AGA) and large for gestational age (LGA) pregnancies.
Reducing trophoblast Deptor RNA levels increased placental mTOR signaling, System A/L transporter expression/activity, and fetal growth in mice. Similarly, human LGA placentas displayed decreased DEPTOR protein levels, inversely correlated to birthweight and BMI.
This is the first report showing that trophoblast-specific DeptorKD is sufficient to activate mTOR signaling, a master regulator of placental function, which increases the TPM System A and L amino acid transporter expression and activity. We also propose that Deptor expression is mechanistically linked to placental mTOR signaling and fetal growth. Furthermore, modulation of DEPTOR signaling may represent a promising approach to improve outcomes in pregnancies characterized by abnormal fetal growth.
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