Metabolic dysfunction induced by HFD + L-NAME preferentially affects hippocampal mitochondria, impacting spatial memory in rats.

High-fat diet-induced metabolic changes are not restricted to the onset of cardiovascular diseases, but also include effects on brain functions related to learning and memory. This study aimed to evaluate mitochondrial markers and function, as well as cognitive function, in a rat model of metabolic dysfunction. Eight-week-old male Wistar rats were subjected to either a control diet or a two-hit protocol combining a high fat diet (HFD) with the nitric oxide synthase inhibitor L-NAME in the drinking water. HFD plus L-NAME induced obesity, hypertension, and increased serum cholesterol. These rats exhibited bioenergetic dysfunction in the hippocampus, characterized by decreased oxygen (O2) consumption related to ATP production, with no changes in H2O2 production. Furthermore, OPA1 protein expression was upregulated in the hippocampus of HFD + L-NAME rats, with no alterations in other morphology-related proteins. Consistently, HFD + L-NAME rats showed disruption of performance in the Morris Water Maze Reference Memory test. The neocortex did not exhibit either bioenergetic changes or alterations in H2O2 production. Calcium uptake rate and retention capacity in the neocortex of HFD + L-NAME rats were not altered. Our results indicate that hippocampal mitochondrial bioenergetic function is disturbed in rats exposed to a HFD plus L-NAME, thus disrupting spatial learning, whereas neocortical function remains unaffected.

4-Hydroxynonenal impairs miRNA maturation in heart failure via Dicer post-translational modification.

BACKGROUND AND AIMS: Developing novel therapies to battle the global public health burden of heart failure remains challenging. This study investigates the underlying mechanisms and potential treatment for 4-hydroxynonenal (4-HNE) deleterious effects in heart failure. METHODS: Biochemical, functional, and histochemical measurements were applied to identify 4-HNE adducts in rat and human failing hearts. In vitro studies were performed to validate 4-HNE targets. RESULTS: 4-HNE, a reactive aldehyde by-product of mitochondrial dysfunction in heart failure, covalently inhibits Dicer, an RNase III endonuclease essential for microRNA (miRNA) biogenesis. 4-HNE inhibition of Dicer impairs miRNA processing. Mechanistically, 4-HNE binds to recombinant human Dicer through an intermolecular interaction that disrupts both activity and stability of Dicer in a concentration- and time-dependent manner. Dithiothreitol neutralization of 4-HNE or replacing 4-HNE-targeted residues in Dicer prevents 4-HNE inhibition of Dicer in vitro. Interestingly, end-stage human failing hearts from three different heart failure aetiologies display defective 4-HNE clearance, decreased Dicer activity, and miRNA biogenesis impairment. Notably, boosting 4-HNE clearance through pharmacological re-activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2) using Alda-1 or its improved orally bioavailable derivative AD-9308 restores Dicer activity. ALDH2 is a major enzyme responsible for 4-HNE removal. Importantly, this response is accompanied by improved miRNA maturation and cardiac function/remodelling in a pre-clinical model of heart failure. CONCLUSIONS: 4-HNE inhibition of Dicer directly impairs miRNA biogenesis in heart failure. Strikingly, decreasing cardiac 4-HNE levels through pharmacological ALDH2 activation is sufficient to re-establish Dicer activity and miRNA biogenesis; thereby representing potential treatment for patients with heart failure.

Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model.

Histidine-containing dipeptides (HCDs) are abundantly expressed in striated muscles. Although important properties have been ascribed to HCDs, including H+ buffering, regulation of Ca2+ transients and protection against oxidative stress, it remains unknown whether they play relevant functions in vivo. To investigate the in vivo roles of HCDs, we developed the first carnosine synthase knockout (CARNS1-/-) rat strain to investigate the impact of an absence of HCDs on skeletal and cardiac muscle function. Male wild-type (WT) and knockout rats (4 months-old) were used. Skeletal muscle function was assessed by an exercise tolerance test, contractile function in situ and muscle buffering capacity in vitro. Cardiac function was assessed in vivo by echocardiography and cardiac electrical activity by electrocardiography. Cardiomyocyte contractile function was assessed in isolated cardiomyocytes by measuring sarcomere contractility, along with the determination of Ca2+ transient. Markers of oxidative stress, mitochondrial function and expression of proteins were also evaluated in cardiac muscle. Animals were supplemented with carnosine (1.8% in drinking water for 12 weeks) in an attempt to rescue tissue HCDs levels and function. CARNS1-/- resulted in the complete absence of carnosine and anserine, but it did not affect exercise capacity, skeletal muscle force production, fatigability or buffering capacity in vitro, indicating that these are not essential for pH regulation and function in skeletal muscle. In cardiac muscle, however, CARNS1-/- resulted in a significant impairment of contractile function, which was confirmed both in vivo and ex vivo in isolated sarcomeres. Impaired systolic and diastolic dysfunction were accompanied by reduced intracellular Ca2+ peaks and slowed Ca2+ removal, but not by increased markers of oxidative stress or impaired mitochondrial respiration. No relevant increases in muscle carnosine content were observed after carnosine supplementation. Results show that a primary function of HCDs in cardiac muscle is the regulation of Ca2+ handling and excitation-contraction coupling.

Benefícios sobre a intensidade da dor, qualidade de vida e incapacidade de mulheres com dismenorreia submetidas a exercícios gerais versus método de pilates: estudo-piloto / Benefits on pain intensity, quality of life, and disability of women with dysmenorrhea undergoing general exercises versus pilates: a pilot study

INTRODUÇÃO: Dismenorreia primária é um distúrbio ginecológico caracterizado por dor relacionada à menstruação, sem causa patológica. OBJETIVO: Verificar e comparar a intensidade da dor, a incapacidade e a qualidade de vida em mulheres com dismenorreia primária submetidas a exercícios gerais versus Pilates. MÉTODOS: Participaram do estudo 14 mulheres aleatorizadas em grupo de exercícios gerais (19,14±1 anos) e de Pilates (20,57±1,8 anos). Ambos os grupos realizaram duas sessões por semana durante 50 minutos, no período de dois meses e meio, totalizando 20 sessões. O grupo de exercícios gerais realizou alongamentos e fortalecimentos dos músculos abdominais, lombares e assoalho pélvico. O grupo de Pilates, por sua vez, praticou exercícios para conscientização de pelve, com contrações do transverso e reto do abdômen, glúteos, períneo e eretores da coluna. As participantes responderam aos questionários de índice de incapacitação de Oswestry para dor lombar, Escala Visual Analógica (EVA), para medir a intensidade da dor e ao Questionário de Qualidade de Vida SF-36, antes e após a intervenção. Os dados foram considerados estatisticamente significantes quando p<0,05. RESULTADOS: Foram encontradas melhoras significativas após a intervenção em ambos os grupos, em todas as avaliações. Em relação à diferença entre os grupos, na avaliação sobre a incapacitação para dor lombar, o grupo de exercícios gerais teve melhor resultado (p<0,003) do que o grupo de Pilates, assim como no domínio de estado da saúde (0,03) do Questionário SF-36. CONCLUSÃO: A prática de exercícios físicos gerais e Pilates por mulheres com dismenorreia podem reduzir a dor e a incapacidade e melhorar a qualidade de vida.

INTRODUCTION: Primary dysmenorrhea is a gynecological disorder characterized by pain associated with menstruation without a pathological cause. OBJECTIVE: To assess and compare pain intensity, disability and quality of life of women with primary dysmenorrhea undergoing general exercise versus Pilate's method. METHODS: This study included 14 women randomlyassigned to general exercise (19.14±1 years) group and Pilates group (20.57±1.8 years). Both groups performed two sessions per week for 50 minutes over two and a half months, totaling 20 sessions. The general exercise group performed stretching and strengthening of the abdominal and lower back muscles, and of pelvic floor. The Pilates group, on the other hand, practiced exercises for pelvis awareness with contractions of transverse and abdomen rectus muscles, buttocks, perineum and erectorsof spine. All the participants responded to the questionnaires of the Oswestry disability index for low back pain; Visual Analogue Scale (VSA) to measure pain intensity; and SF-36 Quality of Life Questionnaire before and after the intervention. Data were considered statistically significant when p<0.05. RESULTS: Significant improvements after the intervention in both groups werefound in all evaluations. With regard to the differences between the groups, in the item of low back pain disability, the general exercise group had better outcomes (p<0.003) than the Pilates group, as well as in the domain of health status (0.03) of the SF-36 Questionnaire. CONCLUSION: Practice of general exercises as well as Pilates's method by women with dysmenorrhea can reduce pain and disability and improve the quality of life.