Biology subjects

Cottet-Rousselle, C.

Publications and source records attributed to Cottet-Rousselle, C..

4 recordsLinked to original sources

bioRxiv2026

Distinct patterns of skeletal muscle wasting and mitochondrial changes following hypoxia and inflammation: associations with physiological phenotype

Skeletal muscle demonstrates a high degree of plasticity that may enable mitochondrial and protein turnover adaptations to environmental stressors such as hypoxia and inflammation. However, the effects of these stressors on skeletal muscle mitochondrial function and proteostatic pathways remain incompletely understood and may depend on muscle phenotype. Given the potential heterogeneity in skeletal muscle responses to these stressors, this study investigated their independent and combined effects on mitochondrial function and protein turnover pathways in oxidative soleus and glycolytic plantaris and assessed the consistency of these responses by comparison with a previous cohort. Adult male Wistar rats were exposed for four weeks to normobaric hypoxia and/or lipopolysaccharide-induced pulmonary inflammation. Mitochondrial respiration, enzymatic activities, markers of mitochondrial function and protein turnover and spontaneous locomotor activity (SLA) were assessed. Pulmonary inflammation predominantly affected soleus, triggering atrophy alongside impaired CI-dependent mitochondrial function, without changes in mitochondrial density. In contrast, plantaris exhibited only atrophy with no mitochondrial alterations in response to inflammation. Hypoxia induced atrophy selectively in plantaris. Notably, the changes following exposure to inflammation and/or hypoxia occurred independently of SLA alterations while the combination of these two stressors did not produce additive effects for most parameters. Comparison with our previous cohort revealed divergent responses that may have been influenced by differences in several physiological characteristics between the two cohorts. These findings demonstrate that hypoxia and pulmonary inflammation induce muscle-specific adaptations and suggest that physiological heterogeneity may contribute to variability in skeletal muscle vulnerability to chronic stress.

physiology↗

bioRxiv2025

Skeletal muscle fibre type determines mitochondrial and metabolic responses to hypoxia and pulmonary inflammation.

BackgroundChronic obstructive pulmonary disease (COPD) patients often experience skeletal muscle dysfunction that may result from a complex combination of mitochondrial dysfunction, metabolic reprogramming and fibre type transitions. Among other factors, pulmonary inflammation and hypoxia contribute to the COPD-associated muscle defects. Nevertheless, the precise molecular mechanisms and their effects across muscles with distinct metabolic profiles remain elusive. This study investigated the independent and combined effects of chronic pulmonary inflammation and chronic hypoxia on mitochondrial function, metabolic enzyme activity and fibre type composition in oxidative (soleus) and glycolytic (plantaris) muscles. MethodsAdult male Wistar rats were subjected to chronic hypoxia (FiO2=10%) and/or chronic pulmonary inflammation (induced by bi-weekly intratracheal instillations of lipopolysaccharides). After 4 weeks of exposure, mitochondria from both soleus and plantaris were isolated to measure oxygen consumption rates, reactive oxygen species (ROS) emission, calcium retention capacity (CRC), respiratory complex activities and fatty acid oxidation capacity. Cross-sections from both muscles were analysed for fibre typology, fibre cross-sectional area (fCSA) as well as succinate dehydrogenase (SDH) and glycerol-3-phosphate dehydrogenase (GPDH) activities. ResultsChronic hypoxia led to a decline in adenosine diphosphate-stimulated complex I (CI) respiration (p<0.01), Hydroxyacyl-Coenzyme A dehydrogenase activity (p<0.01), weight (p<0.05) and fCSA of type IIb fibres (p < 0.05) in plantaris. In contrast, chronic hypoxia increased CI-derived ROS emission (p<0.01) without changes in mitochondrial respiration or mass of soleus. No alterations in fibre typology were noticed in either muscle following the hypoxic exposure. Chronic pulmonary inflammation caused a reduction in mitochondrial CRC and an increase in GPDH activity in type IIa fibres of soleus (p<0.001) without any changes in fibre type distribution. Conversely, chronic pulmonary inflammation induced a downregulation of GPDH activity in plantaris type I and type IIa fibres, in parallel with an elevation in the SDH/GPDH ratio across all fibre types and a rise in the proportion of type IIx fibres. ConclusionsOur results demonstrate fundamental differences in the responses to chronic hypoxia and chronic pulmonary inflammation between soleus and plantaris. While hypoxia affects predominantly the mitochondrial function and mass of plantaris, pulmonary inflammation drives metabolic reprogramming in both muscles that opposes their intrinsic functional specialisation. Additionally, soleus appears more vulnerable to permeability transition pore opening following pulmonary inflammation. Notably, these mitochondrial alterations seem to occur independently of fibre type shifts highlighting the central role of intrinsic mitochondrial maladaptations in the COPD-associated muscle dysfunction.

physiology↗

bioRxiv2025

Preventing neuropathy and improving anti-cancer chemotherapy with a carbazole-based compound

Advances in cancer treatment have led to a steady increase in the rate of disease remission. However, while many treatment-related adverse effects gradually resolve after therapy, chemotherapy-induced peripheral neuropathy (CIPN) often persists, with no means of prevention or direct treatment available. Herein, we present Carba1, a novel bi-functional carbazole that mitigates neuropathy through two distinct mechanisms. First, by interacting with tubulin, Carba1 reduces the required dose of taxanes, widely used chemotherapy drugs notorious for their toxic side effects, including CIPN. Second, Carba1 activates nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, triggering a metabolic rewiring that enhances the resilience of neurons and Schwann cells against chemotherapy-induced toxicity. We demonstrate the neuroprotective efficacy of Carba1 both in vitro, against neurotoxicity induced by paclitaxel (PTX), cisplatin, and bortezomib, and in vivo in a rat model of PTX-induced neuropathy. Importantly, we establish that Carba1 does not compromise the therapeutic efficacy of PTX nor promotes tumor growth. Comparative analyses of Carba1 derivatives further suggest the potential of designing compounds with either dual synergistic and neuroprotective activity or exclusive neuroprotective properties. Altogether, our findings position Carba1 as a promising therapeutic candidate for preventing CIPN, with the potential, if successfully translated to clinical settings, to improve both the quality of life and treatment outcome for cancer patients.

cancer biology↗

bioRxiv2019

Visualization of silver nanoparticle intracellular trafficking revealed nuclear translocation of silver ions leading to nuclear receptor impairment

The impact on human health of the increasing use of silver nanoparticles (AgNPs) in medical devices remains understudied, even though AgNP-containing dressings are known to release silver in the bloodstream leading to accumulation and slow clearance in the liver. Cellular studies have shown the intracellular dissolution of AgNPs within endo-lysosomes followed by Ag(I) binding to biomolecular thiolate-containing molecules. However, the precise subcellular distribution of Ag(I) and the nature of the disrupted physiological pathways remained unknown. Novel imaging approaches enabled us to visualize the trafficking of AgNP-containing lysosomes towards a perinuclear location and a direct nuclear transfer of Ag(I) species with accumulation in the nucleoli. These Ag(I) species impaired nuclear receptor activity, disrupting critical mechanisms of liver physiology in very low dose exposure scenarios, thus justifying further research into defining a framework for the safe use of AgNPs.

pharmacology and toxicology↗