Biology subjects

Handschin, C.

Publications and source records attributed to Handschin, C..

11 recordsLinked to original sources

bioRxiv2025

Exercise Engages Coordinated Neuron-Glia Signaling to Shape Spinal Cord Plasticity

Physical activity induces systemic benefits for brain and muscle function, but how the healthy spinal cord adapts to exercise remains largely unknown. Here, we combine bulk proteomics, single-nucleus RNA sequencing, and cellular communication inference to map exercise- induced molecular adaptations in the mouse lumbar spinal cord. Endurance training elicited robust baseline remodeling, dominated by glial transcriptional changes. Acute exhaustive exercise triggered biphasic responses: widespread metabolic and synaptic gene upregulation at 6 h followed by balanced suppression at 24 h, with trained animals exhibiting enhanced amplitude and faster resolution. Cell-cell communication analysis revealed that exercise reshaped signaling networks in both magnitude and composition. While glia emerged as primary transcriptional responders, cholinergic neurons--despite minimal transcriptional changes--were central signaling hubs, engaging various pathways with astrocytes, oligodendrocyte precursor cells, and oligodendrocytes in a training-dependent and temporally restricted manner. Glial-derived communication further diversified these responses, with astrocytes, oligodendrocytes, and microglia shifting toward pathways supporting synaptic remodeling, axon guidance, and growth factor signaling while dampening inflammatory cues. Together, these findings identify neuron-glia communication as potential driver of spinal cord adaptation to exercise, suggesting pathways through which glial plasticity may serve as a key mediator linking motor activity to spinal cord resilience. Significance StatementExercise confers broad benefits for neural and motor system health, yet how the healthy spinal cord adapts to physical activity is poorly understood. Using multi-omic profiling, we show that endurance training and acute exercise elicit coordinated transcriptional and signaling responses in spinal cord glia, with cholinergic neuron-glia communication emerging as a key upstream driver. These findings identify glial plasticity and neuron-glia crosstalk as a potential mechanism of spinal cord adaptation, providing a foundation for leveraging exercise-based strategies in neurological health and disease.

physiology↗

bioRxiv2025

Muscle Fiber- and Cell Type-Specificity of Training Adaptation in Male Mice

Skeletal muscle possesses extraordinary plasticity of structure, metabolism, and function in response to repeated contractile activity. As a syncytium embedded within a complex microenvironment, muscle relies on the coordination of distinct myonuclear populations and diverse mononucleated cell types. Here, we present a high-resolution single-nucleus RNA-sequencing atlas of 550000 skeletal muscle nuclei, capturing the longitudinal transcriptional responses of 17 distinct myonuclear and 21 mononuclear cell populations at multiple time points after one bout of exhaustive exercise in trained and sedentary mice. The transcriptional programs of these populations are further shaped by training status into divergent adaptive trajectories. A subset of oxidative myonuclei enters a delayed regenerative state post-exercise, reflecting a bifurcated response to a disproportionate metabolic load on fibers during endurance exercise. Prior training accelerates homeostatic recovery and shields oxidative nuclei from exacerbated damage signatures. In parallel, mononucleated cells emerge as the primary mediators of intercellular communication during recovery. Together, this dataset establishes that training adaptation emerges through a coordinated interplay of intrinsic adaptive programs of multicellular remodeling, and provides a foundational resource for mechanistic insights into muscle plasticity.

physiology↗

bioRxiv2025

Autophagy driven by VPS34 enables differentiated cell plasticity and cancer initiation

Differentiated cell plasticity and autophagy are fundamental mechanisms of tissue repair. To investigate their integration to maintain tissue homeostasis, we developed a unique model in which VPS34, the highly conserved class III PI3K that promotes autophagic flux, was inactivated in pancreatic exocrine cells, recognised study models. Using scRNAseq, we found that VPS34-null acinar cells evolved towards a transcriptional identity present at low levels in mouse and human pancreas. Functionally, it unexpectedly prevented transdifferentiation, chronic pancreatitis and precancer initiation triggered by stressors. Mechanistically, the newly differentiated cell state was less susceptible to cancer promotion by oncogenic KRAS, through reduced class I PI3K and increased lysosomal degradation of pro-inflammatory REG3A. This result opens the so far unreachable possibility of strategies for protection from environmentally induced cancer initiation.

pathology↗

bioRxiv2024

Massive reduction of RyR1 in muscle spindles of mice carrying recessive Ryr1 mutations alters proprioception and causes scoliosis

Muscle spindles are stretch receptors lying deep within the muscle belly involved in detecting changes in muscle length and playing a fundamental role in motor control, posture and synchronized gait. They are made up of an external capsule surrounding 3-5 intrafusal muscle fibers and a nuclear bag complex. Dysfunction of muscle spindles leads to abnormal proprioceptor function, which has been linked to aberrant bone and cartilage development, scoliosis, kyphosis and joint contractures. RYR1, the gene encoding the calcium release channel of the sarcoplasmic reticulum, is the most common target of mutations linked to human congenital myopathies, a condition often accompanied by skeleton alterations and joint contractures. So far, the link between RYR1 mutations, altered muscle spindles and skeletal defects has not been investigated. To this end, we investigated heterozygous mice carrying recessive Ryr1 mutations isogenic to those present in a severely affected child. Here we show that: (i) the RyR1 protein localizes to the polar regions of intrafusal fibers and exhibits a doubled row distribution pattern, typical for junctional sarcoplasmic reticulum proteins; (ii) muscle spindles of compound heterozygous mice show structural defects; (iii) RyR1 content in intrafusal muscle fibers from dHT mice is reduced by 54%. Such a massive reduction of mutant RyR1 in intrafusal muscle fibers leads to altered expression of intrafusal fiber proteins, severe scoliosis, alteration of gait and inter limb coordination. These results support the hypothesis that RYR1 mutations not only affect the function of extrafusal muscles, but might also affect that of intrafusal muscles. The latter may be one of the underlying causes of skeletal abnormalities seen in patients affected by recessive RYR1 mutations.

physiology↗

bioRxiv2023

Molecular control of endurance training adaptation in mouse skeletal muscle

Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. While morphological changes in endurance-trained muscles are well-described, the molecular underpinnings of training adaptation are poorly understood. We aimed at defining the molecular signature of a trained muscle and unraveling the training statusdependent responses to an acute bout of exercise. Our results reveal that even though at baseline, the transcriptomes of trained and untrained muscles are very similar, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part mediated by epigenetic modifications. Second, proteomic changes were elicited by different transcriptional modalities. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1) are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that defines muscle plasticity in training. HIGHLIGHTSO_LIVery few persistent transcriptional events define the trained muscle. C_LIO_LIThe training status determines the acute exercise response. C_LIO_LIEpigenetic changes shape the transcriptional specification of trained muscle. C_LIO_LIAbsence of the key regulator PGC-1 causes suboptimal training adaptations. C_LI

physiology↗

bioRxiv2021

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

As global life expectancy continues to climb, maintaining skeletal muscle function is increasingly essential to ensure a good life quality for aging populations. Calorie restriction (CR) is the most potent and reproducible intervention to extend health and lifespan, but is largely unachievable in humans. Therefore, identification of "CR mimetics" has received much attention. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, has been proposed as a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Contrary to our expectation, long-term CR and rapamycin-treated geriatric mice display distinct skeletal muscle gene expression profiles despite both conferring benefits to aging skeletal muscle. Furthermore, CR improved muscle integrity in a mouse with nutrient-insensitive sustained muscle mTORC1 activity and rapamycin provided additive benefits to CR in aging mouse muscles. Therefore, RM and CR exert distinct, compounding effects in aging skeletal muscle, opening the possibility of parallel interventions to counteract muscle aging.

physiology↗

bioRxiv2021

Discovery of lipotoxicity-sensitive transcription factors in non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH.

molecular biology↗

bioRxiv2020

Transcriptomic, proteomic and phosphoproteomic underpinnings of daily exercise performance and Zeitgeber activity of endurance training

Timed physical activity might potentiate the health benefits of training. The underlying signaling events triggered by exercise at different times of the day are, however, poorly understood. Here, we found that time-dependent variations in maximal treadmill exercise capacity of naive mice were associated with energy stores, mostly hepatic glycogen levels. Importantly, running at different times of the day resulted in a vastly different activation of signaling pathways, e.g., related to stress response, vesicular trafficking, repair, and regeneration. Second, voluntary wheel running at the opposite phase of the dark, feeding period surprisingly revealed minimal Zeitgeber (i.e., synchronizing) activity of training. This integrated study provides important insights into the circadian regulation of endurance performance and the control of the circadian clock by exercise. These results are of high importance to understand circadian aspects of training design in athletes and the application of chrono-exercise-based interventions in patients. HighlightsO_LIMaximal endurance performance is greater in the early morning C_LIO_LITimed exercise differentially alters the muscle transcriptome and (phospho)-proteome C_LIO_LIMorning exercise triggers energy provisioning and tissue regeneration C_LIO_LIEvening exercise activates stress-related and catabolic pathways C_LIO_LITraining exerts poor Zeitgeber activity on the muscle and liver clocks C_LI

physiology↗

bioRxiv2020

RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates

The peroxisome-proliferator-activated receptor-{gamma} coactivator-1 (PGC-1) integrates environmental cues by controlling complex transcriptional networks in various metabolically active tissues. However, it is unclear how a transcriptional coregulator coordinates dynamic biological programs in response to multifaceted stimuli such as endurance training or fasting. Here, we discovered a central function of the poorly understood C-terminal domain (CTD) of PGC-1 to bind RNAs and assemble multi-protein complexes. Surprisingly, in addition to controlling the coupling of transcription and processing of target genes, RNA binding is indispensable for the recruitment of PGC-1 to chromatin into liquid-like nuclear condensates, which compartmentalize and regulate active transcription. These results demonstrate a hitherto unsuspected molecular mechanism by which complexity in the regulation of large transcriptional networks by PGC-1 is achieved. These findings are not only essential for the basic understanding of transcriptional coregulator-driven control of biological programs, but will also help to devise new strategies to modulate these processes in pathological contexts in which PGC-1 function is dysregulated, such as type 2 diabetes, cardiovascular diseases or skeletal muscle wasting.

molecular biology↗

bioRxiv2020

Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes

Aims/hypothesisIncreased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. MethodsPlasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific PGC-1 knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PGC-1A and ESRRA in the expression of the BCAA gene set. Radiolabeled leucine was used to analyze the impact of ERR knockdown on leucine oxidation. ResultsImpairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37-56% after an OGTT in the NGT group, whereas no changes were detected in individuals with T2D. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of BCAT2, BCKDH complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing PGC-1, 61% of the analyzed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific PGC-1 knockout mice. ESRRA (encoding estrogen-related receptor , ERR) silencing completely abrogated the PGC-1-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretationMetabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease of circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via a PGC-1 is ERR-dependent. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LICirculating levels of BCAA are elevated in type 2 diabetes. C_LIO_LIPGC-1 is involved in the transcription of the BCAA gene set. C_LI What is the key question?O_LIDoes metabolic inflexibility associated with type 2 diabetes encompass BCAA homeostasis and PGC-1 mediated transcription of the BCAA gene set? C_LI What are the new findings?O_LIBCAA homeostasis is further compromised by a glucose challenge in type 2 diabetes. C_LIO_LIAn OGTT reveals coordinated regulation between BCAA metabolites, blood glucose, and HbA1c levels. C_LIO_LIERR is essential for PGC-1-mediated BCAA gene expression in primary human myotubes. C_LI How might this impact on clinical practice in the foreseeable future?O_LIAn OGTT can be used to underscore impairments in BCAA metabolism. These findings suggest that interventions targeting the PGC-1/ ERR axis may improve BCAA homeostasis. C_LI

physiology↗

bioRxiv2018

PGC-1α regulates mitochondrial calcium homeostasis, SR stress and cell death to mitigate skeletal muscle aging

Age-related impairment of muscle function severely affects the health of an increasing elderly population. While causality and the underlying mechanisms remain poorly understood, exercise is an efficient intervention to blunt these aging effects. We thus investigated the role of the peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1), a potent regulator of mitochondrial function and exercise adaptation, in skeletal muscle during aging. We demonstrate that PGC-1 overexpression improves mitochondrial dynamics and calcium buffering in an estrogen-related receptor (ERR)-dependent manner. Moreover, we show that sarcoplasmic reticulum stress is attenuated by PGC-1. As a result, PGC-1 prevents tubular aggregate formation and fiber apoptosis in old muscle. Similarly, the pro-apoptotic effects of ceramide and thapsigargin were blunted by PGC-1 in muscle cells. Accordingly, mice with muscle-specific gain- and loss-of-function of PGC-1 exhibit a delayed and premature aging phenotype, respectively. Together, our data reveal a key protective effect of PGC-1 on muscle function and overall health span in aging.\n\nStatement of significanceThe loss of muscle function in aging results in a massive impairment in life quality, e.g. by reducing motor function, strength, endurance, the ability to perform daily tasks or social interactions. Unfortunately, the mechanistic aspects underlying age-related muscle disorders remain poorly understood and treatments improving the disease are extremely limited. We now show that PGC-1, a transcriptional coactivator, is a key regulator of mitochondrial calcium homeostasis, cellular stress and death, all of which are linked to muscle aging and dysfunction. As a result, inhibition of the age-related decline in muscle PGC-1 considerably reduces aging of muscle and constitutes a promising target to prevent and treat the deterioration of muscle function in the elderly.\n\nAbbreviationsBNIP3, BCL2/Adenovirus E1B 19kDa interacting protein 3; Cpt1b, carnitine palmitoyltransferase 1B; CSQ1, calsequestrin 1; Drp1, dynamin-related protein 1; ER stress, endoplasmic reticulum stress; ERR, estrogen-related receptor ; Fis1, fission 1; GRP75, Glucose-Regulated Protein 75; IGFBP5, insulin like growth factor binding protein 5; IP3, inositol 1,4,5-trisphosphate; IP3R1, inositol 1,4,5-trisphosphate receptor type 1; Letm1, leucine zipper and EF-hand containing transmembrane protein 1; MAMs, mitochondria-associated ER membranes; Mcad, medium-chain acyl-CoA dehydrogenase; Opa1, optic atrophy 1; OXPHOS, oxidative phosphorylation; PGC-1, peroxisome proliferator-activated receptor {gamma} coactivator 1; pH2AX, phospho-H2A Histone Family Member X; ppRB, phospho-preproretinoblastoma-associated protein; Puma, BCL2 Binding Component 3; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; TA, tibialis anterior; TBP, TATA binding protein; TPG, thapsigargin; Ucp3, uncoupling protein 3; VDAC, voltage-dependent anion channel; XBP1, X-Box Binding Protein 1; Xiap, X-linked inhibitor of apoptosis protein

cell biology↗