Proteomics of muscle aging in women

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Etude protéomique du vieillissement musculaire chez la femme post-ménopausée

National audienceIntroduction et Méthodes : Une approche protéomique a été développée afin identifier de nouveaux biomarqueurs du vieillissement musculaire (sarcopénie). Des extraits totaux et sarcoplasmiques ont été préparés à partir de femmes ménopausées matures (54 ans) et âgées (78 ans). Sur un total de 1919 spots, 133 sont exprimés de façon différentielle chez les femmes âgées par rapport aux femmes matures, et la spectrométrie de masse (nanoLC-MS/MS) a permis d’identifier 74 protéines différentes. Résultats : On observe d'importantes modifications du métabolisme énergétique cytosolique (TPIS, PYGM, GPDA, créatine-kinase) et mitochondrial (pyruvate-déshydrogénase, aconitase, COX, NADH-déshydrogénase). Certaines protéines différentiellement exprimées correspondent à des protéines myofibrillaires (myosine light-chaînes, troponines T, myozenin). Tout ceci peut expliquer les modifications des propriétés contractiles chez la personne âgée. Les autres protéines montrent des perturbations dans les processus de cytoprotection et de détoxification, comme une régulation différentielle de plusieurs chaperons moléculaires (HSPA9, HSPA1A), l'homéostasie ionique (sélénium-binding protein) et le stress du réticulum endoplasmique (sarcalumenin, calséquestrine). De plus, l’expression de protéines impliquées dans la protéolyse est augmentée (VCP, UBA1, Calpain Small subunit-1). Nous avons aussi remarqué une régulation négative des protéines impliquées dans l’édition de l’ARN (apobec2) et la traduction mitochondriale (TuFM). Conclusion : Plusieurs biomarqueurs identifiés dans cette analyse étaient auparavant non reconnus comme différentiellement exprimés dans le muscle âgé, et peuvent représenter de nouveaux points de départ pour élucider certains des mécanismes de la sarcopénie

Beneficial effects of endurance exercise training on skeletal muscle microvasculature in sickle cell disease patients

Epub ahead of printSickle cell disease (SCD) is a genetic hemoglobinopathy leading to two major clinical manifestations: severe chronic hemolytic anemia and iterative vaso-occlusive crises. SCD is also accompanied by profound muscle microvascular remodeling. The beneficial effects of endurance training on microvasculature are widely known. The aim of this study was to evaluate the effects of an endurance training program on microvasculature of skeletal muscle in SCD patients. A biopsy of the vastus lateralis muscle and submaximal incremental exercise were performed before and after the training period. Of the forty randomized SCD patients, complete data sets from 32 were obtained. The training group (n=15) followed a personalized moderate-intensity endurance training program, while the non-training (n=17) group maintained a normal lifestyle. Training consisted of three 40-minute cycle ergometer exercise sessions per week for 8 weeks. Histological analysis highlighted microvascular benefits in the training SCD patients compared to non-training patients, including increases in capillary density (CD) (P = .003), number of capillaries around a fiber (CAF) (P = .015) and functional exchange surface (LC/PF) (P < .0001). Conversely, no significant between-group difference was found in the morphology of capillaries. Indexes of physical ability also improved in the training patients. The moderate-intensity endurance exercise training program improved the muscle capillary network and partly reversed the microvascular defects commonly observed in skeletal muscle of SCD patients. This trial was registered at www.clinicaltrials.gov as #NCT02571088

UBE2L3, a Partner of MuRF1/TRIM63, Is Involved in the Degradation of Myofibrillar Actin and Myosin

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1-UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy

Etude protéomique du vieillissement musculaire chez la femme post-ménopausée

Etude protéomique du vieillissement musculaire chez la femme post-ménopausée. 6. colloque Protéolyse Cellulaire de la Société Française de Biochimie et Biologie Moléculaire (SFBBM