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Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells (1,2). Senescent cells accumulate in various tissues and organs with ageing (3) and have been hypothesized to disrupt tissue structure and function because of the components they secrete (4,5). However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, [p16.sup.Ink4a], to design a novel transgene, INK-ATTAC, for inducible elimination of [p16.sup.Ink4a]-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes [p16.sup.Ink4a]-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye-in which [p16.sup.Ink4a] contributes to the acquisition of age-related pathologies, life-long removal of [p16.sup.Ink4a]-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan., To examine the role of cellular senescence in ageing and age-related pathologies, we designed a transgenic strategy for the clearance of senescent cells in mice. We based our approach on [...]

The objective of this study was to examine the effects of short-term exercise training, myostatin inhibition (PF-354), and exercise + PF-354, all relative to a vehicle control, on performance and metabolic measures in 24-month-old mice. At study termination, PF-354--treated mice exhibited significantly greater muscle weights. Performance measures revealed that exercise + PF-354 increased treadmill running time and distance to exhaustion (more than twofold) and increased habitual activity. Measures of strength were not different: however, all treatment groups demonstrated more than 30% reductions in muscle fatigue. Metabolic measures showed that basal metabolic rates were higher in PF-354-- and exercise + PF-354--treated mice, and exercise and exercise + PF-354 groups exhibited significantly greater insulin sensitivity. PF-354 was associated with decreased Smad3 phosphorylation and increased peroxisome proliferator-activated receptor gamma coactivator-1[alpha] expression and, similar to exercise, decreased MuRF-1. The data suggest that the combination of exercise training and myostatin blockade may significantly improve physical function and whole-body metabolism in older individuals. Key Words: Sarcopenia--Insulin resistance--Strength--Exercise capacity.

The 2023 Padua Days of Muscle and Mobility Medicine (Pdm3) were held from March 29th to April 1st, 2023. Most of the abstracts were published electronically in the European Journal of Translational Myology (EJTM) 33 (1) 2023. Here we report the complete book of abstracts that confirms the interest of more than 150 scientists and clinicians from Austria, Bulgaria, Canada, Denmark, France, Georgia, Germany, Iceland, Ireland, Italy, Mongolia, Norway, Russia, Slovakia, Slovenia, Spain, Switzerland, The Netherlands and USA to gather to the Hotel Petrarca of Thermae of Euganean Hills, Padua, Italy for contributing and attending the Pdm3 (https://www.youtube.com/watch?v=zC02D4uPWRg). The 2023 Pdm3 started March 29th in the historic Aula Guariento of thePadua Galilean Academy of Letters, Arts and Sciences with the Lecture of Prof. Carlo Reggiani and ended in the late afternoon with the Lecture of Professor Terje Lømo after introductory words of Professor Stefano Schiaffino. The program followed in the Hotel Petrarca Conferenece Halls from March 30 to April 1, 2023. The extended topic interests of specialists in basic myology sciences and clinicians, collected under the umbrella neologism of Mobility Medicine, is stressed also by expansion of Sections of the EJTM Editorial Board (https://www.pagepressjournals.org/index.php/bam/board). We hope that Speakers of the 2023 Pdm3 and readers of EJTM will submit "EJTM Communications" to the European Journal of Translational Myology (PAGEpress, Pavia, Italy) by May 31, 2023 and/or invited review and original articles for the 2023 special issue: "Pdm3" of Diagnostics, MDPI, Basel, Switzerland due September 30, 2023. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPAR[gamma] in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, by increasing the expression and release of adiponectin, an adipokine that activates the fuel-sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPAR[gamma]-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 [micro]M troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 [micro]M, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-D-glucose uptake and the oxidation of exogenous [[sup.14]C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min after the administration of a single dose of troglitazone (10 mg/kg, ip). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPAR[gamma] to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPAR[gamma]-mediated gene transcription. acetyl-coenzyme A carboxylase; adiponectin; diabetes; insulin sensitivity; metabolism

Parkington, Jascha D., Adam P. Siebert, Nathan K. LeBrasseur, and Roger A. Fielding. Differential activation of mTOR signaling by contractile activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 285: R1086-R1090, 2003. First published July 24, 2003; 10.1152/ ajpregu.00324.2003.--The cellular mechanisms by which contractile activity stimulates skeletal muscle hypertrophy are beginning to be elucidated and appear to include activation of the phosphatidylinositol 3-kinase signaling substrate mammalian target of rapamycin (mTOR). We examined the time course and location of mTOR phosphorylation in response to an acute bout of contractile activity. Rat hindlimb muscle contractile activity was elicited by high-frequency electrical Stimulation (HFES) of the sciatic nerve. Plantaris (Pla), tibialis anterior (TA), and soleus (Sol) muscles from stimulated and control limbs were collected immediately or 6 h after stimulation. HFES resulted in mTOR phosphorylation immediately after (3.4.[+ or -] 0.9-fold, P < 0.01) contractile activity in Pla, whereas TA was unchanged compared with controls, mTOR phosphorylation remained elevated in Pla (3.6 [+ or -] 0.6-fold) and increased in TA (4.6[+ or -] 0.9-fold, P < 0.05) 6 h after HFES. Interestingly, mTOR activation occurred predominantly in fibers expressing type IIa but not type I myosin heavy chain isoform. Furthermore, HFES induced modest ribosomal protein $6 kinase phosphorylation immediately after exercise in Pla (0.4 [+ or -] 0.1-fold, P < 0.05) but not TA and more markedly 6 h after in both Pla and TA (1.4 [+ or -] 0.4-fold vs. 2.4 [+ or -] 0.3-fold, respectively, P < 0.01). Akt/PKB phosphorylation was similar to controls at both time points. These results suggest that mTOR signaling is increased after a single bout of muscle contractile activity. Despite reports that mTOR is activated downstream of Akt/PKB, in this study, HFES induced mTOR signaling independent of Akt/ PKB phosphorylation. Fiber type-dependent mTOR phosphorylation may be a molecular basis by which some fiber types are more susceptible to contraction-induced hypertrophy. exercise; hypertrophy; ribosomal protein S6 kinase; Akt

Putative roles of neuregulin (NRG) and the ErbB receptors in skeletal muscle biology include myogenesis, ACh receptor expression, and glucose transport. To date, however, the physiological regulation of NRG/ErbB signaling has not been examined. We tested the hypothesis that contractile activity in vivo induces NRG/ ErbB activation. Rat hindlimb muscle contraction was elicited with a single bout of electrical stimulation (RX) or treadmill running (EX). Western blot and immunofiuorescence confirmed the expression of multiple NRG isoforms and the ErbB2, ErbB3, and ErbB4 receptors in adult skeletal muscle. Both RX and EX significantly increased phosphorylation of all NRG receptors. Furthermore, contraction induced a shift in the expression profile of NRG, consistent with proteolytic processing of a transmembrane isoform. Thus two distinct modes of exercise activated processing of NRG with concomitant stimulation of ErbB2, ErbB3, and ErbB4 signaling in vivo. To our knowledge, this is the first demonstration of physiological regulation of NRG/ErbB signaling in any organ and implicates this pathway in the metabolic and proliferative responses of skeletal muscle to exercise. exercise; growth factor; receptor tyrosine kinase

Background: Delirium is underdiagnosed in clinical practice and is not routinely coded for billing. Manual chart review can be used to identify the occurrence of delirium; however, it is labor-intensive and impractical for large-scale studies. Natural language processing (NLP) has the capability to process raw text in electronic health records (EHRs) and determine the meaning of the information. We developed and validated NLP algorithms to automatically identify the occurrence of delirium from EHRs.Methods: This study used a randomly selected cohort from the population-based Mayo Clinic Biobank (N = 300, age ≥65). We adopted the standardized evidence-based framework confusion assessment method (CAM) to develop and evaluate NLP algorithms to identify the occurrence of delirium using clinical notes in EHRs. Two NLP algorithms were developed based on CAM criteria: one based on the original CAM (NLP-CAM; delirium vs no delirium) and another based on our modified CAM (NLP-mCAM; definite, possible, and no delirium). The sensitivity, specificity, and accuracy were used for concordance in delirium status between NLP algorithms and manual chart review as the gold standard. The prevalence of delirium cases was examined using International Classification of Diseases, 9th Revision (ICD-9), NLP-CAM, and NLP-mCAM.Results: NLP-CAM demonstrated a sensitivity, specificity, and accuracy of 0.919, 1.000, and 0.967, respectively. NLP-mCAM demonstrated sensitivity, specificity, and accuracy of 0.827, 0.913, and 0.827, respectively. The prevalence analysis of delirium showed that the NLP-CAM algorithm identified 12 651 (9.4%) delirium patients, the NLP-mCAM algorithm identified 20 611 (15.3%) definite delirium cases, and 10 762 (8.0%) possible cases.Conclusions: NLP algorithms based on the standardized evidence-based CAM framework demonstrated high performance in delineating delirium status in an expeditious and cost-effective manner. [ABSTRACT FROM AUTHOR]