Experiments reported here tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12–16months. We developed the rationale for these experiments on the basis that angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR) promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts as a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. We have previously reported that biased ligands acting at the AT1R promote β-arrestin-2 signaling increasing cardiac contractility and reducing maladaptations in a mouse model of dilated cardiomyopathy. Although there is evidence that ang II induces maladaptive senescence in the cardiovascular system, a role for β-arrestin-2 signaling has not been studied in aging. By echocardiography, we found that compared to controls aged KO mice exhibited enlarged left atria and left ventricular diameters as well as depressed contractility parameters with preserved ejection fraction. Aged KO also exhibited depressed relaxation parameters when compared to WT controls at the same age. Moreover, cardiac dysfunction in aged KO mice was correlated with alterations in the phosphorylation of myofilament proteins, such as cardiac myosin binding protein-C, and myosin regulatory light chain. Our evidence provides novel insights into a role for β-arrestin-2 as an important signaling mechanism that preserves cardiac function during aging.

RESUMO O objetivo desta pesquisa foi avaliar os efeitos de uma intervenção manipulativa sobre a atividade eletromiográfica dos músculos paraverterbais e a intensidade da dor na coluna lombar imediatamente e 30 minutos após sua realização em indivíduos com dor lombar crônica mecânica. Foram avaliados 38 indivíduos, distribuídos aleatoriamente em dois grupos: o que recebeu a técnica de manipulação vertebral global (n=20) e o controle (n=18), que permanecia em decúbito lateral por dez segundos sobre cada lado do corpo. O sinal eletromiográfico dos paravertebrais ao nível L4-L5 direito e esquerdo foi coletado durante três ciclos do movimento de flexão-relaxamento-extensão do tronco. Nos intervalos entre os ciclos, os participantes relataram a intensidade de dor através da Escala Visual Analógica (EVA 100 mm). Foi observada redução significativa na intensidade da dor no grupo que recebeu a manipulação, ao contrário do grupo controle, em que a pontuação na EVA aumentou. O tamanho do efeito na intensidade da dor foi de 1,0 e 0,9 logo após a manipulação e 30 minutos depois. A razão de flexão/relaxamento (RFR) aumentou no grupo que foi submetido à manipulação, mas permaneceu inalterada no grupo controle. A RFR exibiu tamanhos de 0,6 e 0,5 entre os grupos nas duas avaliações. Foi possível constatar efeitos da manipulação nessas duas variáveis e sua continuidade no intervalo observado, concluindo-se que eles perduram pelo menos durante esse tempo.

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Muscular and anatomical changes are mostly responsible for patella femoral syndrome (PFPS). Knowing that the quadriceps muscles are very important in stabilizing the patella, studies have questioned the influence of the Vastus Medialis Obliquus (VMO) in the patellar stabilization avoiding the PFPS. Many researchers have investigated the use of taping as a means of muscle activation. Objective: The present study aimed to analyze the use of functional taping to activate the VMO during the squat exercise. Method: The activity of the VMO and Vastus Lateralis (VL) was assessed by electromyography during squats and squats with adduction using functional taping. The sample, composed of 39 individuals, was divided into four groups: males and females, both separated into sedentary and athletic types. Results: Although greater activation of the VMO has been found in comparison with the VL, with the applied methodology and variables, we could not demonstrate a statistical difference between groups in squats with and without the use of functional taping. However, it is important to emphasize that the lack of difference in the activation of VMO during squats with adduction and taping suggests a positive effect of the taping in muscle activation. This result is very important in the treatment of acute injuries where active movement is limited. Conclusion: Future studies should be done with other electromyography parameters and reflex activation in order to investigate the actual role of functional taping in muscle activation.

Diabetes mellitus is a metabolic disorder that can generate tissue damage through several pathways. Alteration and dysfunction of skeletal muscle are reported including respiratory muscles, which may compromise respiratory parameters in diabetic patients. We have aimed to evaluate the diaphragm muscle contractility, tissue remodeling, oxidative stress, and inflammatory parameters from 30 day streptozotocin-treated rats. The diaphragm contractility was assessed using isolated muscle, tissue remodeling using histology and zymography techniques, and tissue oxidative stress and inflammatory parameters by enzyme activity assay. Our data revealed in the diabetes mellitus group an increase in maximum tetanic force (4.82 ± 0.13 versus 4.24 ± 0.18 N/cm2 (p = 0.015)) and fatigue resistance (139.16 ± 10.78 versus 62.25 ± 4.45 s (p < 0.001)), reduction of 35.4% in muscle trophism (p < 0.001), increase of 32.6% of collagen deposition (p = 0.007), reduction of 21.3% in N-acetylglucosaminidase activity (p < 0.001), and increase of 246.7% of catalase activity (p = 0.002) without changes in reactive oxygen species (p = 0.518) and tissue lipid peroxidation (p = 0.664). All observed changes are attributed to the poor glycemic control (471.20 ± 16.91 versus 80.00 ± 3.42 mg/dL (p < 0.001)), which caused defective tissue regeneration and increased catalase activity as a compensatory mechanism.

β-arrestin-2 (ARRB2) has an integral role in G-protein-coupled receptor regulation and signaling. Our lab has reported that biased ligands acting at the AT1-R promote ARRB2 signaling that increases contractility and reduces maladaptations in dilated cardiomyopathy. Our hypothesis is that ARRB2 is necessary for the physiological eccentric cardiac hypertrophic response associated with voluntary exercise. Methods and Results: Our study compared ARRB2 knockout (KO) and age matched FVBN control mice (NTG). Twelve-week-old age mice were divided into 4 groups. For a 6-week period ARRB2-KO and NTG were either sedentary or subjected to voluntary running. Records from wheels were obtained continuously through Wi-Fi and the data were analyzed weekly. Before exercise, baseline echocardiographic analyses were performed showing no apparent differences in cardiac function among the groups. Initially no differences were found in running parameters between ARRB2-KO and controls. However, beginning in the third week through the end of the exercise duration we found a decrease in the distance covered in ARRB2KO females compared with NTG females. After 6-weeks of exercise there was an increase in LA diameter, LV mass, LVIDd and HW/TL ratio only in NTG female compared with sedentary group suggesting ARRB2 sex-related differences in response to voluntary exercise. Although ARRB2 KO in C57/BL mice has been shown to alter myofilament Ca-sensitivity, we found no changes in myofilament Ca-sensitivity and post-translational modifications among all four groups. Conclusion: Our data suggest that ARRB2 is required for physiological hypertrophy caused by voluntary exercise only in female but not in male mice. Further studies are required to test whether ARRB2 is required for development of more stressful physiological hypertrophy during involuntary training regimens such as swimming or treadmill.

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.