Biology subjects

Delezie, J.

Publications and source records attributed to Delezie, J..

4 recordsLinked to original sources

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↗

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↗

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↗