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Sarcopenia, a disorder marked by muscle loss and dysfunction, is a global health concern, particularly in aging populations. Sarcopenia is intricately related to various health conditions, including obesity, dysphagia, and frailty, which underscores the complexity. Despite recent advances in metabolomics and other omics data for early detection and treatment, the precise characterization and diagnosis of sarcopenia remains challenging. In the present review we provide an overview of the complex metabolic mechanisms that underlie sarcopenia, with particular emphasis on protein, lipid, carbohydrate, and bone metabolism. The review highlights the importance of leucine and other amino acids in promoting muscle protein synthesis and clarifies the critical role played by amino acid metabolism in preserving muscular health. In addition, the review provides insights regarding lipid metabolism on sarcopenia, with an emphasis on the effects of inflammation and insulin resistance. The development of sarcopenia is largely influenced by insulin resistance, especially with regard to glucose metabolism. Overall, the review emphasizes the complex relationship between bone and muscle health by highlighting the interaction between sarcopenia and bone metabolism. Furthermore, the review outlines various therapeutic approaches and potential biomarkers for diagnosing sarcopenia. These include pharmacological strategies such as hormone replacement therapy and anabolic steroids as well as lifestyle modifications such as exercise, nutrition, and dietary changes. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases including cardiac arrhythmias lead to fatal events in patients with coronary artery disease; however, clinical associations from echocardiography, electrocardiography (ECG), and biomarkers remain unknown. We sought to identify the factors that may be related to elevated QRS intervals in patients with risk for coronary artery disease. In this study, we performed analysis of clinical data from 503 patients divided into two groups, i.e., patients with either 50% coronary artery stenosis. We further examined patients with elevated ECG parameters such as QRS > 100 ms and QTc > 440 ms. Patients with >50% coronary artery stenosis exhibited significant increases in age, triglycerides, and troponin levels. Further, ECG parameters demonstrated increased QRS and QTc durations, while echocardiographic parameters highlighted a decrease in ejection fraction (EF) and fractional shortening (FS). Patients with QTc > 440 ms exhibited increased brain natriuretic peptide and creatinine levels with a decrease in estimated glomerular filtration rate clearance rates. Patients with QRS > 100 ms had greater left ventricular (LV) mass and LV internal diameter in systole and diastole. Multimodal logistic regression showed significant relation between QTc, age, and creatinine. These findings suggest that patients with significant coronary stenosis may have lower EF and FS with prolonged QRS intervals, demonstrating greater risk for arrhythmic events. Key words: coronary artery disease, creatinine, left ventricular mass, heart, electrocardiography echo. Les maladies cardiovasculaires, y compris les arythmies cardiaques, menent a des evenements mortels chez les patients atteints de coronaropathie, mais leur association en clinique avec les donnees d'echocardiographie et d'electrocardiographie (ECG) ainsi qu'en matiere de biomarqueurs demeure inconnue. Nous avons cherche a determiner les facteurs qui pourraient etre lies a une augmentation de la duree du QRS de patients exposes a un risque accru de coronaropathie. Cette etude portait sur les donnees cliniques issues de 503 patients repartis dans deux groupes : stenose des arteres coronaires 50 %. Nous avons en outre etudie les patients qui presentaient des parametres ECG accrus comme une duree du QRS > 100 ms et de l'intervalle QTc > 440 ms. Les patients presentant une stenose coronarienne >50 % etaient aussi plus ages avec des taux de triglycerides et de troponine plus eleves. De plus, les parametres ECG montraient une augmentation de la duree des QRS et des intervalles QTc, tandis que les parametres echocardiographiques mettaient en evidence une diminution de la fraction d'ejection (FE) et de la fraction de raccourcissement (FR). Les patients avec un intervalley QTc > 440 ms presentaient une augmentation des taux de peptide natriuretique cerebral et de creatinine avec une diminution de la clairance (eGFR). Les patients avec une duree des QRS > 100 ms presentaient une augmentation de la masse du ventricule gauche (VG), avec un diametre interne du VG plus eleve en systole comme en diastole. La regression logistique multimodale a montre un lien robuste entre la duree du QTc, l'age et la creatininemie. Ces resultats laissent entendre que les patients presentant une stenose des arteres coronaires importante pourraient aussi presenter une diminution de la FE et du FR avec une prolongation de la duree du QRS, ce qui montre un risque accru de presenter des evenements arythmiques. [Traduit par la Redaction] Mots-cles: coronaropathie, creatinine, masse du ventricule gauche, electrocardiographie, echocardiographie., Introduction Cardiac arrhythmias are a leading determinant of cardiovascular related deaths in the USA and worldwide (Khurshid et al. 2018; Srinivasan and Schilling 2018). Arrhythmias are primarily detected using electrocardiography [...]

Skeletal muscle injury affects the quality of life in many pathologies, including volumetric muscle loss, contusion injury, and aging. We hypothesized that the nicotinamide phosphoribosyltransferase (Nampt) activator P7C3 improves muscle repair following injury. In the present study, we tested the effect of P7C3 (1‐anilino‐3‐(3,6‐dibromocarbazol‐9‐yl) propan‐2‐ol) on chemically induced muscle injury. Muscle injury was induced by injecting 50 µL 1.2% barium chloride (BaCl2) into the tibialis anterior (TA) muscle in C57Bl/6J wild‐type male mice. Mice were then treated with either 10 mg/kg body weight of P7C3 or Vehicle intraperitoneally for 7 days and assessed for histological, biochemical, and molecular changes. In the present study, we show that the acute BaCl2‐induced TA muscle injury was robust and the P7C3‐treated mice displayed a significant increase in the total number of myonuclei and blood vessels, and decreased serum CK activity compared with vehicle‐treated mice. The specificity of P7C3 was evaluated using Nampt+/− mice, which did not display any significant difference in muscle repair capacity among treated groups. RNA‐sequencing analysis of the injured TA muscles displayed 368 and 212 genes to be exclusively expressed in P7C3 and Veh‐treated mice, respectively. There was an increase in the expression of genes involved in cellular processes, inflammatory response, angiogenesis, and muscle development in P7C3 versus Veh‐treated mice. Conversely, there is a decrease in muscle structure and function, myeloid cell differentiation, glutathione, and oxidation–reduction, drug metabolism, and circadian rhythm signaling pathways. Chromatin immunoprecipitation‐quantitative polymerase chain reaction (qPCR) and reverse transcription‐qPCR analyses identified increased Pax7, Myf5, MyoD, and Myogenin expression in P7C3‐treated mice. Increased histone lysine (H3K) methylation and acetylation were observed in P7C3‐treated mice, with significant upregulation in inflammatory markers. Moreover, P7C3 treatment significantly increased the myotube fusion index in the BaCl2‐injured human skeletal muscle in vitro. P7C3 also inhibited the lipopolysaccharide‐induced inflammatory response and mitochondrial membrane potential of RAW 264.7 macrophage cells. Overall, we demonstrate that P7C3 activates muscle stem cells and enhances muscle injury repair with increased angiogenesis. [ABSTRACT FROM AUTHOR]

Glucocorticoids, such as fluticasone propionate (FP), are used for the treatment of inflammation and alleviation of nasal symptoms and allergies, and as an antipruritic. However, both short- and long-term therapeutic use of glucocorticoids can lead to muscle weakness and atrophy. In the present study, we evaluated the feasibility of the nanodelivery of FP with poly(DL-lactide-co-glycolide) (PLGA) and tested in vitro function. FP-loaded PLGA nanoparticles were prepared via nanoprecipitation and morphological characteristics were studied via scanning electron microscopy. FP- loaded nanoparticles demonstrated an encapsulation efficiency of 68.6% [+ or -] 0.5% with a drug loading capacity of 4.6% [+ or -] 0.04%, were 128.8 [+ or -] 0.6 nm in diameter with a polydispersity index of 0.07 [+ or -] 0.008, and displayed a zeta potential of - 19.4 [+ or -] 0.7. A sustained in vitro drug release pattern was observed for up to 7 days. The use of fluticasone nanoparticle decreased lipopolysaccharide (LPS)-induced lactate dehydrogenase release compared with LPS alone in C2C12 treated cells. FP also decreased expression of LPS-induced inflammatory genes in C2C12 treated cells as compared with LPS alone. Taken together, the present study demonstrates in vitro feasibility of PLGA-FP nanoparticle delivery to the skeletal muscle cells, which may be beneficial for treating inflammation. Key words: fluticasone propionate, glucocorticoid, PLGA, nanoparticles, skeletal muscle. Les glucocorticoides, tels que le propionate de fluticasone (PF), sont utilises dans le traitement de l'inflammation et l'attenuation de symptomes nasaux, d'allergies et comme antiprurigineux. Toutefois, l'utilisation therapeutique de glucocorticoides a court comme a long terme peut mener a de la fatigue et de l'atrophie musculaires. Dans la presente etude, nous avons evalue la faisabilite de la nanoliberation de PF avec de l'acide poly(DL-lactide-co-glycolide) (APLG) et evalue le fonctionnement in vitro. Nous avons prepare des nanoparticules d'APLG chargees de PF a l'aide de la nanopreciptitation et nous avons etudie les caracteristiques morphologiques a l'aide de la microscopie electronique par balayage. Nous avons observe que les nanoparticules chargees de PF presentaient une efficacite d'encapsulation de 68,6 [+ or -] 0,5 % avec une capacite de chargement du medicament de 4,6 [+ or -] 0,04 %, avaient un diametre de 128,8 [+ or -]0,6 nm in avec un indice de polydipersion de 0,07 [+ or -] 0,008, et presentaient un potentiel zeta de -19,4 [+ or -] 0,7. Nous avons observe un patron de liberation du medicament in vitro soutenu pendant jusqu'a 7 jours. L'utilisation de nanoparticules de fluticasone entrainait une diminution de la liberation de deshydrogenase lactique provoquee par les lipopolysaccharides (LPS) par rapport aux LPS seules dans des cellules exposees au C2C12. Le PF entrainait aussi une diminution de l'expression de genes inflammatoires actives par les LPS dans des cellules exposees au C2C12 par rapport aux LPS seules. Dans l'ensemble, la presente etude montre la faisabilite in vitro de la liberation de nanoparticules d'APLG-PF vers les cellules de muscle squelettique, ce qui pourrait apporter des bienfaits dans le traitement de l'inflammation. [Traduit par la Redaction] Mots-cles : propionate de fluticasone, glucocorticoide, acide poly(DL-lactide- co-glycolide), nanoparticules, muscle squelettique., Introduction Glucocorticoids are used for the treatment of inflammation and pain related to skeletal muscle injury, wound healing, and arthritis (Bijlsma 2012; Klein 2015; Vyvey 2010). However, both short- and [...]

Glucocorticoids are utilized for their anti-inflammatory properties in the skeletal muscle and arthritis. However, the major drawback of use of glucocorticoids is that it leads to senescence and toxicity. Therefore, based on the idea that decreasing particle size allows for increased surface area and bioavailability of the drug, in the present study, we hypothesized that nanodelivery of dexamethasone will offer increased efficacy and decreased toxicity. The dexamethasone-loaded poly(lactic-coglycolic acid) (PLGA) nanoparticles were prepared using nanoprecipitation method. The morphological characteristics of the nanoparticles were studied under scanning electron microscope. The particle size of nanoparticles was 217.5 [+ or -] 19.99 nm with polydispersity index of 0.14 [+ or -] 0.07. The nanoparticles encapsulation efficiency was 34.57% [+ or -] 1.99% with in vitro drug release profile exhibiting a sustained release pattern over 10 days. We identified improved skeletal muscle myoblast performance with improved closure of the wound along with increased cell viability at 10 nmol/L nano-dexamethasone-PLGA. However, dexamethasone solution (1 [micro]mol/L) was injurious to cells because the migration efficiency was decreased. In addition, the use of dexamethasone nanoparticles decreased lipopolysaccharide-induced lactate dehydrogenase release compared with dexamethasone solution. Taken together, the present study clearly demonstrates that delivery of PLGA-dexamethasone nanoparticles to the skeletal muscle cells is beneficial for treating inflammation and skeletal muscle function. Key words: dexamethasone, PLGA, nanoparticles, skeletal muscle. Les glucocorticoides sont utilises pour leurs proprietes anti-inflammatoires dans le muscle squelettique et l'arthrite. Cependant, le principal probleme de l'utilisation des glucocorticoides tient au fait qu'elle mene a de la senescence et de la toxicite. Par consequent, a partir de l'idee qu'en diminuant la taille des particules on augmente la surface de contact et la biodisponibilite du medicament, dans la presente etude, nous avons formule une hypothese selon laquelle l'administration de nanoparticules de dexamethasone permet d'en augmenter l'efficacite et d'en diminuer la toxicite. Nous avons prepare des nanoparticules d'acide poly(lactique co-glycolique) [ou PLGA pour << poly(lactic-co-glycolic acid)>>] chargee de dexamethasone a l'aide de la methode de nanoprecipitation. Nous avons etudie les caracteristiques morphologiques des nanoparticules a l'aide de la microscopie electronique par balayage. Les nanoparticules avaient une taille de 217,5 [+ or -] 19,99 nm avec un indice de polydispersion de 0,14 [+ or -] 0,07. L'efficacite de l'encapsulation des nanoparticules etait de 34,57 [+ or -] 1,99 % avec un profil in vitro de liberation du medicament presentant un schema de liberation soutenue sur 10 jours. Avec le complexe PLGA-nano-dexamethasone a 10 nmol/L, nous avons observe une amelioration de la performance des myoblastes du muscle squelettique avec une amelioration de la fermeture de plaie ainsi qu'une augmentation de la vitalite des cellules. Toutefois, une solution de dexamethasone (1 [micro]mol/L) provoquait des lesions cellulaires en raison d'une diminution de l'efficacite de la migration. De plus, l'utilisation de nanoparticules de dexamethasone entrainait une diminution de la liberation de lipopolysaccharides produite par la deshydrogenase lactique plus marquee qu'avec la solution de dexamethasone. Dans l'ensemble, la presente etude montre que l'administration de nanoparticules de PLGA-dexamethasone aux cellules de muscle squelettique est avantageuse pour traiter l'inflammation et le fonctionnement du muscle squelettique. [Traduit par la Redaction] Mots-cles: dexamethasone, PLGA, nanoparticules, muscle squelettique., Introduction Dexamethasone and other glucocorticoids are used for the treatment of inflammation and pain related to skeletal muscle injury, wound healing, and arthritis (Bijlsma 2012; Klein 2015; Vyvey 2010). However, [...]

Sarcopenia is an age-related, involuntary loss of skeletal muscle mass and strength. Alzheimer’s disease (AD) is the most common cause of dementia in elderly adults. To date, no effective cures for sarcopenia and AD are available. Physical and cognitive impairments are two major causes of disability in the elderly population, which severely decrease their quality of life and increase their economic burden. Clinically, sarcopenia is strongly associated with AD. However, the underlying factors for this association remain unknown. Mechanistic studies on muscle–brain crosstalk during cognitive impairment might shed light on new insights and novel therapeutic approaches for combating cognitive decline and AD. In this review, we summarize the latest studies emphasizing the association between sarcopenia and cognitive impairment. The underlying mechanisms involved in muscle–brain crosstalk and the potential implications of such crosstalk are discussed. Finally, future directions for drug development to improve age-related cognitive impairment and AD-related cognitive dysfunction are also explored. [ABSTRACT FROM AUTHOR]

The failure of muscle to repair after injury during aging may be a major contributor to muscle mass loss. We recently generated muscle progenitor cells (MPCs) from human-induced pluripotent stem-cell (iPSC) cell lines using small molecules, CHIR99021 and Givinostat (Givi-MPCs) sequentially. Here, we test whether the chemokines overexpressed in injured endothelial cells direct MPC migration to the site by binding to their receptor, ITGA4. ITGA4 was heavily expressed in Givi-MPCs. To study the effects on the mobilization of Givi-MPCs, ITGA4 was knocked down by an ITGA4 shRNA lentiviral vector. With and without ITGA4 knocked down, cell migration in vitro and cell mobilization in vivo using aged NOD scid gamma (NSG) mice and mdx/scid mice were analyzed. The migration of shITGA4-Givi-MPCs was significantly impaired, as shown in a wound-healing assay. The knockdown of ITGA4 impaired the migration of Givi-MPCs towards human aortic endothelial cells (HAECs), in which CX3CL1 and VCAM-1 were up-regulated by the treatment of TNF-α compared with scramble ones using a transwell system. MPCs expressing ITGA4 sensed chemokines secreted by endothelial cells at the injury site as a chemoattracting signal to migrate to the injured muscle. The mobilization of Givi-MPCs was mediated by the ligand–receptor interaction, which facilitated their engraftment for repairing the sarcopenic muscle with injury. [ABSTRACT FROM AUTHOR]

Cardiomyocyte N-methyl-D-aspartate receptor-1 (NMDA-R1) activation induces mitochondrial dysfunction. Matrix metalloproteinase protease (MMP) induction is a negative regulator of mitochondrial function. Elevated levels of homocysteine [hyperhomocysteinemia (HHCY)] activate latent MMPs and causes myocardial contractile abnormalities. HHCY is associated with mitochondrial dysfunction. We tested the hypothesis that HHCY activates myocyte mitochondrial MMP (mtMMP), induces mitochondrial permeability transition (MPT), and causes contractile dysfunction by agonizing NMDA-R1. The C57BL/6J mice were administered homocystinemia (1.8 g/l) in drinking water to induce HHCY. NMDA-R 1 expression was detected by Western blot and confocal microscopy. Localization of MMP-9 in the mitochondria was determined using confocal microscopy. Ultrastructural analysis of the isolated myocyte was determined by electron microscopy. Mitochondrial permeability was measured by a decrease in light absorbance at 540 nm using the spectrophotometer. The effect of MK-801 (NMDA-R1 inhibitor), GM-6001 (MMP inhibitor), and cyclosporine A (MPT inhibitor) on myocyte contractility and calcium transients was evaluated using the IonOptix video edge track detection system and fura 2-AM. Our results demonstrate that HHCY activated the mtMMP-9 and caused MPT by agonizing NMDA-R1. A significant decrease in percent cell shortening, maximal rate of contraction (-dL/dt), and maximal rate of relaxation (+dL/dt) was observed in HHCY. The decay of calcium transient amplitude was faster in the wild type compared with HHCY. Furthermore, the HHCY-induced decrease in percent cell shortening, -dL/dt, and +dL/dt was attenuated in the mice treated with MK-801, GM-6001, and cyclosporin A. We conclude that HHCY activates mtMMP-9 and induces MPT, leading to myocyte mechanical dysfunction by agonizing NMDA-R1. myocyte; calcium; mitochondrial permeability; N-methyl-D-aspartate receptor-1; arrhythmogenesis

The activity of the voltage-sensitive [K.sup.+] (Kv) channels varies as a function of the intracellular redox state and metabolism, and several Kv channels act as oxygen sensors. However, the mechanisms underlying the metabolic and redox regulation of these channels remain unclear. In this study we investigated the regulation of Kv channels by pyridine nucleotides. Heterologous expression of Kv[alpha] 1.5 in COS-7 cells led to the appearance of noninactivating currents. Inclusion of 0.1-1 mM NA[D.sup.+] or 0.03-0.5 mM NAD[P.sup.+] in the internal solution of the patch pipette did not affect Kv currents. However, 0.5 and 1 mM NA[D.sup.+] and 0.1 and 0.5 mM NAD[P.sup.+] prevented inactivation of Kv currents in cells transfected with Kv[alpaha] 1.5 and Kv[beta] 1.3 and shifted the voltage dependence of activation to depolarized potentials. The Kv[beta]-dependent inactivation of Kv[alpha] currents was also decreased by internal pipette perfusion of the cell with 1 mM NA[D.sup.+]. The Kv[alpha]1.5-Kv[beta]1.3 currents were unaffected by the internal application of 0.1 mM NADPH or 0.1 or 1 mM NADH. Excised inside-out patches from cells expressing Kv[alpha]1.5-Kv[beta] 1.3 showed transient single-channel activity. The mean open time and the open probability of these currents were increased by the inclusion of 1 mM NA[D.sup.+] in the perfusate. These results suggest that NAD[(P).sup.+] prevents Kv[beta]-mediated inactivation of Kv currents and provide a novel mechanism by which pyridine nucleotides could regulate specific [K.sup.+] currents as a function of the cellular redox state INAD(P)H-to-NAD[(P).sup.+] ratio]. Shaker potassium ion channels: Kv[beta] subunits: patch clamp: aldo-keto reductase: COS-7 cells

We investigated differences in L-type C[a.sup.2+] current (I[sub.ca]) between infant (INF, 1-12 mo old), young adult (YAD, 14-18 yr old), and older adult (AD) myocytes from biopsies of right atrial appendages. Basal I[sub.Ca] was smaller in INF myocytes (1.2 [+ or -] 0.1 pA/pF, n = 29, 6 [+ or -] 1 mo old, 11 patients) than in YAD (2.5 [+ or -] 0.2 pA/pF, n = 20, 16 [+ or -] 1 yr old, 5 patients) or AD (2.6 [+ or -] 0.3 pA/pF, n = 19, 66 [+ or -] 3 yr old, 9 patients) myocytes (P < 0.05). Maximal I[sub.Ca] produced by isoproterenol (Iso) was similar in INF, YAD, and AD ceils: 8.4 [+ or -] 1.1, 9.6 [+ or -] 1.0, and 9.2 [+ or -] 1.3 pA/pF, respectively. Efficacy ([E.sub.max]) was larger in INF (607 [+ or -] 50%) than for YAD (371 [+ or -] 29%) or AD (455 [+ or -] 12%) myocytes. Potency (E[C.sub.50]) was 8- to 10-fold higher in AD (0.82 [+ or -] 0.09 nM) or YAD (0.41 [+ or -] 0.14 nM) than in INF (7.6 [+ or -] 3.5 nM) myocytes. Protein levels were similar for [G.sub.i][[alpha].sub.2] but much greater for [G.sub.i][[alpha].sub.3] in INF than in AD or YAD atrial tissue. When [G.sub.i][[alpha].sub.3] activity was inhibited by inclusion of a [G.sub.i[alpha]3] COOH-terminal decapeptide in the pipette, basal [I.sub.Ca] and the response to 10 nM Iso were increased in INF, but not in YAD, cells. We propose that basal [I.sub.Ca] and the response to low-dose [beta]-adrenergic stimulation are inhibited in INF (but not YAD or AD) cells as a result of constitutive inhibitory effects of [G.sub.i][[alpha].sub.3]. [beta]-adrenergic receptors; human atrium; atrial function; isoproterenol

The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool. [ABSTRACT FROM AUTHOR]