Biology subjects

Granata, C.

Publications and source records attributed to Granata, C..

15 recordsLinked to original sources

bioRxiv2026

Structural topology shapes regional roles in neuronal avalanche initiation and termination

Whole-brain dynamics unfold as fast, discrete, transient events known as, neuronal avalanches, whose propagation is constrained by the connectome, that is, the large-scale scaffolding of structural connections wiring the brain. However, the role of the connectome in determining the topographies of the start and end of these transient cascades remains unclear. Leveraging resting-state Magnetoencephalography (MEG) recordings and diffusion magnetic resonance imaging (dMRI) tractography across 42 healthy individuals, we examined whether the structural architecture of white matter tracts dictates the spatial origins and the end of cortical avalanches. We found that the probability of triggering and finishing an avalanche is strongly related to the structural nodal strength, showing a positive correlation that is highly robust to non-parametric spatial permutation testing and bootstrapping. This structure-function coupling is highly stable and robust across different activation thresholds, demonstrating that the choice of avalanche extraction threshold does not drive or alter our main findings. Collectively, our results suggest that structural properties determine a region's propensity to initiate and terminate neuronal avalanches.

neuroscience↗

bioRxiv2026

Temporal persistence and structural organization of neuronal avalanche dynamics

Brain activity can be understood as a sequence of neuronal avalanches, i.e., transient episodes of coordinated activation that emerge across scales, from individual neurons and local networks to whole-brain dynamics. Avalanches are typically characterized by features such as size, duration, number of active components, and the silent time separating consecutive events. Although these features have been extensively characterized through their marginal distributions, their temporal organization and dependence on the underlying brain architecture remain poorly understood, leaving us without a framework for embedding neuronal avalanches within slower brain dynamics. Here, we analyzed eyes-closed resting-state magnetoencephalography recordings and the corresponding structural connectomes from 30 healthy participants to investigate the dynamics of avalanche sizes and silent times. We found that large avalanches preferentially followed short silent times, whereas small avalanches were more likely to occur after long silent periods. Based on the empirical joint distributions of avalanche size and silent time, we could define four types of events occurring above chance levels (avalanche large or small, preceding pause long or short). Mixed categories, combining a small value of one feature with a large value of the other, occurred more frequently than expected, while same-category events happened less often than chance. Furthermore, consecutive events tended to remain in the same category, a phenomenon referred to as persistence. We next investigated whether a brain region's connectivity profile shapes its propensity to participate in avalanches of different sizes. More strongly connected regions participated most often in small avalanches, whereas weakly connected regions were preferentially recruited during large avalanches. This pattern may reflect the greater sensitivity of highly connected hubs to fluctuations propagating through the network, resulting in frequent but spatially contained events. By contrast, the recruitment of more peripheral regions may require broader and stronger collective activity, occurring only during rarer, large-scale avalanches. In contrast, regional participation showed no clear association with the silent time preceding an avalanche. Together, these findings show that neuronal avalanches are neither temporally independent nor anatomically unconstrained: their sequence retains a memory of preceding events, while structural topology shapes which regions are recruited as avalanches grow. By connecting avalanche dynamics with slower temporal organization and the structural connectome, our results provide a multiscale framework for understanding how transient events are embedded within ongoing brain activity.

neuroscience↗

bioRxiv2026

Departure from OFF-State Microstate Dynamics Tracks Levodopa Response in Parkinson's Disease

Although dopaminergic therapies in Parkinsons disease primarily restore dopamine within nigrostriatal circuits, symptoms are better indexed by whole-brain dynamics than by local activity. In this manuscript, we hypothesize that L-Dopa therapy affects whole-brain dynamics alike, which in turn relate to clinical improvement. To test this hypothesis, we conducted a repeated-measures, source-reconstructed MEG study in 13 bradykinetic-dominant PD patients, recording resting-state cortical activity OFF medication and [~]1 hour after levodopa administration (ON). We characterize brain dynamics using a microstate framework, in which transition probabilities between microstates are used to contrast pathological OFF-state dynamics with those in the ON-state. Microstate dynamics were stable within medication states but reconfigured by L-Dopa, with greater departures from the OFF-state pattern associated, at the individual level, with larger clinical improvements. Our results suggest that individualized changes in microstate dynamics may serve as a neurophysiological marker of dopaminergic responsiveness.

neuroscience↗

bioRxiv2026

Bioenergetic profiling of fresh human kidney tissue reveals compensatory metabolic adaptation and intrinsic mitochondrial dysfunction in diabetes

The kidney is a highly energetic organ, requiring substantial ATP production through mitochondrial oxidative phosphorylation to support tubular reabsorption. Metabolic reprogramming and impaired mitochondrial function are implicated in diabetic kidney disease, yet direct assessment of mitochondrial respiratory flux in the human kidney has been constrained by limited access to freshly obtained tissue. Consequently, much of the evidence supporting altered renal mitochondrial function in diabetes derives from animal models that do not fully recapitulate the human condition. We established a workflow for real-time bioenergetic profiling of fresh kidney cortex obtained during nephrectomy from living individuals with diabetes and preserved kidney function. Mitochondrial respiration, electron transport system activity and tubular mitochondrial morphology were compared with age- and sex-matched, histopathologically normal non-diabetic controls. High-resolution respirometry revealed increased mitochondrial respiratory flux in permeabilised diabetic kidney cortex. In contrast, mitochondria isolated from the same tissue exhibited reduced respiratory capacity and impaired complex I activity. Quantitative analysis of tubular cells demonstrated increased mitochondrial volume density together with greater mitochondrial fragmentation in diabetes. These findings reveal that the human kidney undergoes substantial metabolic adaptation early in diabetes, before measurable loss of kidney function. Increased tissue-level respiratory flux despite intrinsic mitochondrial impairment suggests that expansion and remodelling of the mitochondrial network may initially compensate for reduced organelle efficiency and sustain the kidneys high energetic demands. This compensatory state may, however, increase metabolic stress and vulnerability to subsequent kidney injury. To our knowledge, this study provides the first direct tissue-level functional evidence that mitochondrial metabolism is reprogrammed in the human kidney in diabetes before measurable kidney dysfunction develops. It defines an early bioenergetic signature characterised by tissue hypermetabolism despite impaired mitochondria-specific respiratory capacity, challenging the concept that diabetes produces a uniform decline in renal mitochondrial function. Failure to sustain this adaptive state may represent a critical transition towards diabetic kidney disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/740003v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@101eb51org.highwire.dtl.DTLVardef@100187corg.highwire.dtl.DTLVardef@1478af2org.highwire.dtl.DTLVardef@1f31fc1_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryDiabetes drives early metabolic reprogramming of the human kidney before measurable kidney dysfunction

pathology↗

bioRxiv2026

Hormone-Dependent Microstates and the Reconfiguration of Resting-State Dynamics across the Menstrual Cycle

While behavioral fluctuations across the menstrual cycle (MC) are well-documented, the neural underpinnings of these changes remain elusive. This study investigated the hypothesis that cyclic variations in sex hormones modulate large-scale brain activation patterns. To test this, longitudinal magnetoencephalographic (MEG) recordings were acquired and source reconstructed from 24 naturally cycling women across three distinct MC phases: early follicular, peri-ovulatory, and mid-luteal. Microstate analysis was employed to characterize large-scale cortical dynamics as "visits" to specific global configurations (i.e., maps) of brain activity. Our results revealed significant variations in the occurrence of specific microstate maps, particularly between the early follicular and mid-luteal phases. Furthermore, the occurrence of these specific configurations was significantly associated with fluctuations in hormone levels. Critically, both the hormonal levels and microstate dynamics were predictive of individual longitudinal changes in psychological well-being. These findings propose a neurophysiological substrate for the behavioral effects of hormonal cycling, identifying specific topographic maps whose dynamics are sensitive to the hormonal profile and carry predictive power for psychological health. Collectively, these results underscore the necessity of accounting for the MC in neuroimaging research and introduce a novel framework for defining microstates (Hormone-Dependent Microstates - HDMs) with respect to slowly changing dynamical properties across a month-long timescale.

neuroscience↗

bioRxiv2024

Criticality explains structure-function relationships in the human brain

Healthy brain exhibits a rich dynamical repertoire, with flexible spatiotemporal patterns replays on both microscopic and macroscopic scales. How do fixed structural connections yield a diverse range of dynamic patterns in spontaneous brain activity? We hypothesize that the observed relationship between empirical structure and functional patterns is best explained when the microscopic neuronal dynamics is close to a critical regime. Using a modular Spiking Neuronal Network model based on empirical connectomes, we posit that multiple stored functional patterns can transiently reoccur when the system operates near a critical regime, generating realistic brain dynamics and structural-functional relationships. The connections in the model are chosen as to force the network to learn and propagate suited modular spatiotemporal patterns. To test our hypothesis, we employ magnetoencephalography and tractography data from five healthy individuals. We show that the critical regime of the model is able to generate realistic features, and demonstrate the relevance of near-critical regimes for physiological brain activity.

neuroscience↗

bioRxiv2024

High-resolution respirometry reveals altered mammalian tissue ketone body oxidation in different cardiometabolic diseases

Background and aimsReduced mitochondrial function has been implicated in metabolic disorders like type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), which are tightly linked to insulin resistance and impaired metabolic flexibility. However, the contribution of the ketone bodies (KBs) {beta}-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear. MethodsTargeted high-resolution respirometry protocols were applied to detect the differential contribution of HBA and ACA to OXPHOS capacity in heart, skeletal muscle, kidney, and liver of distinct human and mouse cohorts with T2D, obesity, and MASLD. ResultsIn humans with T2D, KB-driven mitochondrial OXPHOS capacity was [~]30% lower in the heart (p<0.05) and skeletal muscle (p<0.05) compared to non-diabetic controls. The relative contribution of KB to maximal OXPHOS capacity in T2D was also lower in both the heart ([~]25%, p<0.05) and skeletal muscle ([~]50%, p<0.05). Similarly, in kidney cortex from high-fat diet-induced obese mice, both the absolute and relative contribution of KB to OXPHOS capacity was [~]15% lower (p<0.05). Finally, hepatic HBA-driven mitochondrial OXPHOS capacity was 29% lower (p<0.05) in obese humans with MASLD compared to humans without MASLD. ConclusionsMitochondrial KB-driven OXPHOS capacity is impaired in insulin resistant states in various organs in absolute and relative terms, likely reflecting impaired mitochondrial metabolic flexibility. Our data suggest that KB respirometry can provide a sensitive readout of impaired mitochondrial function in diabetes, obesity, and MASLD.

cell biology↗

bioRxiv2023

Deep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease

Changes in mitochondrial energy metabolism are thought to be central to the development of diabetic kidney disease (DKD); however, whether this response is explicitly driven by systemic glucose concentrations remains unknown. Here, we show that titrating blood glucose concentrations in vivo directly impacts mitochondrial morphology and bioenergetics and remodels the mitochondrial proteome in the kidney in early DKD. Mitoproteomic analysis revealed profound metabolic disturbances induced by severe hyperglycemia, including upregulation of enzymes involved in the TCA cycle and fatty acid metabolism, enhanced ketogenesis as well as dysregulation of the mitochondrial SLC25 carrier family. Untargeted metabolomics and lipidomics confirmed the enrichment of TCA cycle metabolites, an increase in triglyceride concentrations, and extensive and specific cardiolipin remodeling. Lowering blood glucose to moderate hyperglycemia stabilized all three omic landscapes, partially prevented changes in mitochondrial morphology and bioenergetics, and improved kidney injury. This study demonstrates altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and provides new insights into kidney metabolism, which has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.

cell biology↗

bioRxiv2022

Single-fibre proteomics reveals a greater fibre-type specific mitochondrial remodelling with moderate than high-intensity training.

Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide new insights into fibre-specific mitochondrial differences in human skeletal muscle before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and highlight that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were stoichiometrically linked to changes in markers of mitochondrial content.

physiology↗

bioRxiv2021

Exercise and training regulation of autophagy markers in human and rodent skeletal muscle.

Autophagy is a key intracellular mechanism by which cells degrade old or dysfunctional proteins and organelles. In skeletal muscle, evidence suggests that exercise increases autophagosome content and autophagy flux. However, the exercise-induced response seems to differ between rodents and humans, and little is known about how different exercise prescription parameters may affect these results. The present study utilised skeletal muscle samples obtained from four different experimental studies using rats and humans. Here we show that following exercise, in the soleus muscle of Wistar rats, there is an increase in LC3B-I protein levels (+ 109%) immediately after exercise, and a subsequent increase in LC3B-II protein levels (+ 97%) 3 hours into the recovery. Conversely, in human skeletal muscle, there is an immediate exercise-induced decrease in LC3B-II protein levels (- 24%), independent of whether exercise is performed below or above the maximal lactate steady state, which returns to baseline 3.5 hours following recovery, while no change in LC3B-I protein levels is observed. p62 protein levels did not change in neither rats nor humans following exercise. By employing an ex vivo autophagy flux assay previously used in rodents we demonstrate that the exercise-induced decrease in LC3B-II protein levels in humans does not reflect a decreased autophagy flux. Instead, effect size analyses suggest a modest-to-large increase in autophagy flux following exercise that lasts up to 24 hours. Our findings suggest that exercise-induced changes in autophagosome content markers differ between rodents and humans, and that exercise-induced decrease in LC3B-II protein levels do not reflect autophagy flux level.

molecular biology↗

bioRxiv2021

Methodological considerations when assessing mitochondrial respiration and biomarkers for mitochondrial content in human skeletal muscle

BackgroundThe assessment of mitochondrial respiration and mitochondrial content are two common measurements in the fields of skeletal muscle research and exercise science. However, to verify the validity of the observed changes in both mitochondrial respiration and mitochondrial content following an intervention such as exercise training, it is important to determine the reliability and reproducibility of the experimental design and/or techniques employed. We examined the repeatability of widely used methodologies for assessing mitochondrial respiration and mitochondrial content, respectively; the measurement of maximal mitochondrial oxidative phosphorylation in permeabilized muscle fibres using high-resolution respirometry, and the measurement of citrate synthase activity as a biomarker for mitochondrial content in a microplate with spectrophotometer. ResultFor mitochondrial respiration, the coefficient of variation for repeated measurements using muscle sampled from same biopsy decreased from 12.7% to 11% when measured in triplicate with outliers excluded, rather than in duplicate. The coefficient of variation was 9.7% for repeated muscle biopsies sampled across two separated days. For measurements of citrate synthase activity, the coefficient of variation was 3.5% of three technical repeats on the same plate, 10.2% for duplicate analyses using the same muscle lysate when conducted in the same day, and 30.5% when conducted four weeks apart. ConclusionWe have provided evidence for important technical considerations when measuring mitochondrial respiration with human skeletal muscle: 1) the relatively large technical variability can be reduced by increasing technical repeats and excluding outliers; 2) the biological variability and absolute mitochondrial respiration value of the participants should be considered when estimating the required sample size; 3) a new threshold of 15% for the increase in respiration rate after the addition of cytochrome c test for testing mitochondrial outer membrane integrity. When analysing citrate synthase activity, our evidence suggests it is important to consider the following: 1) all samples from the same study should be homogenized and measured at the same time using the same batch of freshly made chemical reagents; 2) biological variability should be considered when detecting small change in mitochondrial content; 3) the relative change should be used to compare the outcomes from different studies.

physiology↗

bioRxiv2021

Multi-omics reveal intricate network of mitochondrial adaptations to training in human skeletal muscle

Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible and inexpensive therapeutic intervention improving mitochondrial bioenergetics and quality of life. By combining a multi-omics approach with biochemical and in silico normalization, we removed the bias arising from the training-induced increase in human skeletal muscle mitochondrial content to unearth an intricate and previously undemonstrated network of differentially prioritized mitochondrial adaptations. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the increase in mitochondrial content. We demonstrate that enhancing electron flow to oxidative phosphorylation (OXPHOS) is more important to improve ATP generation than increasing the abundance of the OXPHOS machinery, and that training-induced supercomplex formation does not confer enhancements in mitochondrial bioenergetics. Our study provides a new analytical approach allowing unbiased and in-depth investigations of training-induced mitochondrial adaptations, challenging our current understanding and calling for careful reinterpretation of previous findings.

cell biology↗

bioRxiv2020

Brain networks and cognitive impairment in Parkinson's disease

AimThe aim of the present study is to investigate the relations between both functional connectivity and brain networks with cognitive decline, in patients with Parkinsons disease (PD). IntroductionPD phenotype is not limited to motor impairment but, rather, a wide range of non-motor disturbances can occur, cognitive impairment being one of the commonest. However, how the large-scale organization of brain activity differs in cognitively impaired patients, as opposed to cognitively preserved ones, remains poorly understood. MethodsStarting from source-reconstructed resting-state magnetoencephalography data, we applied the PLM to estimate functional connectivity, globally and between brain areas, in PD patients with and without cognitive impairment (respectively PD-CI and PD-NC), as compared to healthy subjects (HS). Furthermore, using graph analysis, we characterized the alterations in brain network topology and related these, as well as the functional connectivity, to cognitive performance. ResultsWe found reduced global and nodal PLM in several temporal (fusiform gyrus, Heschls gyrus and inferior temporal gyrus), parietal (postcentral gyrus), and occipital (lingual gyrus) areas within the left hemisphere, in the gamma band, in PD-CI patients, as compared to PD-NC and HS. With regard to the global topological features, PD-CI patients, as compared to HS and PD-NC patients, showed differences in multi frequencies bands (delta, alpha, gamma) in the Leaf fraction, Tree hierarchy (both higher in PD-CI) and Diameter (lower in PD-CI). Finally, we found statistically significant correlations between the MoCA test and both the Diameter in delta band and the Tree Hierarchy in the alpha band. ConclusionOur work points to specific large-scale rearrangements that occur selectively in cognitively compromised PD patients and correlated to cognitive impairment.

neuroscience↗

bioRxiv2020

Loss of integration of brain netwroks after one night of sleep deprivation underlies worsening of attentive functions

The topology of brain networks changes according to environmental demands and can be described within the framework of graph theory. We hypothesized that 24-hours long sleep deprivation (SD) causes functional rearrangements of the brain topology so as to impair optimal communication, and that such rearrangements relate to the performance in specific cognitive tasks, namely the ones specifically requiring attention. Thirty-two young men underwent resting-state MEG recording and assessments of attention and switching abilities before and after SD. We found loss of integration of brain network and a worsening of attention but not of switching abilities. These results show that brain network changes due to SD affect switching abilities, worsened attention and induce large-scale rearrangements in the functional networks.

neuroscience↗

bioRxiv2019

High-intensity interval training blunts exercise-induced changes in markers of mitochondrial biogenesis in human skeletal muscle

Exercise-induced increases in peroxisome proliferator-activated receptor {gamma} coactivator-1 (PGC-1) and p53 protein content in the nucleus mediate the initial phase of exercise-induced mitochondrial biogenesis. Here we investigated if exercise-induced increases in these and other markers of mitochondrial biogenesis were altered after 40 sessions of twice-daily high-volume high-intensity interval training (HVT) in human skeletal muscle. Vastus lateralis muscle biopsies were collected from 10 healthy recreationally active participants before, immediately post, and 3h after a session of HIIE performed at the same absolute exercise intensity before and after HVT (Pre-HVT and Post-HVT, respectively). The protein content of common markers of exercise-induced mitochondrial biogenesis were assessed in nuclear- and cytosolic-enriched fractions by immunoblotting; mRNA contents of key transcription factors and mitochondrial genes were assessed by qPCR. Despite exercise-induced increases in PGC-1, p53, and plant homeodomain finger-containing protein 20 (PHF20) protein content, the phosphorylation of p53 and acetyl-CoA carboxylase (p-p53Ser15 and p-ACCSer79, respectively), and PGC-1 mRNA Pre-HVT, no significant changes were observed Post-HVT. Forty sessions of twice-daily high-intensity interval training blunted all of the measured exercise-induced molecular events associated with mitochondrial biogenesis that were observed Pre-HVT. Future studies should determine if this loss relates to the decrease in relative exercise intensity, habituation to the same exercise stimulus, or a combination of both.

physiology↗