Reciprocal communication between FAPs and muscle cells via distinct extracellular vesicle miRNAs in muscle regeneration.

Muscle regeneration is a complex process relying on precise teamwork between multiple cell types, including muscle stem cells (MuSCs) and fibroadipogenic progenitors (FAPs). FAPs are also the main source of intramuscular adipose tissue (IMAT). Muscles without FAPs exhibit decreased IMAT infiltration but also deficient muscle regeneration, indicating the importance of FAPs in the repair process. Here, we demonstrate the presence of bidirectional crosstalk between FAPs and MuSCs via their secretion of extracellular vesicles (EVs) containing distinct clusters of miRNAs that is crucial for normal muscle regeneration. Thus, after acute muscle injury, there is activation of FAPs leading to a transient rise in IMAT. These FAPs also release EVs enriched with a selected group of miRNAs, a number of which come from an imprinted region on chromosome 12. The most abundant of these is miR-127-3p, which targets the sphingosine-1-phosphate receptor S1pr3 and activates myogenesis. Indeed, intramuscular injection of EVs from immortalized FAPs speeds regeneration of injured muscle. In late stages of muscle repair, in a feedback loop, MuSCs and their derived myoblasts/myotubes secrete EVs enriched in miR-206-3p and miR-27a/b-3p. The miRNAs repress FAP adipogenesis, allowing full muscle regeneration. Together, the reciprocal communication between FAPs and muscle cells via miRNAs in their secreted EVs plays a critical role in limiting IMAT infiltration while stimulating muscle regeneration, hence providing an important mechanism for skeletal muscle repair and homeostasis.

Effects of Resistance Exercise on Slow-Twitch Soleus Muscle of Infarcted Rats.

Although current guidelines recommend resistance exercise in combination with aerobic training to increase muscle strength and prevent skeletal muscle loss during cardiac remodeling, its effects are not clear. In this study, we evaluated the effects of resistance training on cardiac remodeling and the soleus muscle in long-term myocardial infarction (MI) rats. METHODS: Three months after MI induction, male Wistar rats were assigned to Sham (n = 14), MI (n = 9), and resistance exercised MI (R-MI, n = 13) groups. The rats trained three times a week for 12 weeks on a climbing ladder. An echocardiogram was performed before and after training. Protein expression of the insulin-like growth factor (IGF)-1/protein kinase B (Akt)/rapamycin target complex (mTOR) pathway was analyzed by Western blot. RESULTS: Mortality rate was higher in MI than Sham; in the R-MI group, mortality rate was between that in MI and Sham and did not differ significantly from either group. Exercise increased maximal load capacity without changing cardiac structure and left ventricular function in infarcted rats. Infarction size did not differ between infarcted groups. Catalase activity was lower in MI than Sham and glutathione peroxidase lower in MI than Sham and R-MI. Protein expression of p70S6K was lower in MI than Sham and p-FoxO3 was lower in MI than Sham and R-MI. Energy metabolism did not differ between groups, except for higher phosphofrutokinase activity in R-MI than MI. CONCLUSION: Resistance exercise is safe and increases muscle strength regardless structural and functional cardiac changes in myocardial-infarcted rats. This exercise modality attenuates soleus glycolytic metabolism changes and improves the expression of proteins required for protein turnover and antioxidant response.

Tissue differences in the exosomal/small extracellular vesicle proteome and their potential as indicators of altered tissue metabolism.

Exosomes/small extracellular vesicles (sEVs) can serve as multifactorial mediators of cell-to-cell communication through their miRNA and protein cargo. Quantitative proteomic analysis of five cell lines representing metabolically important tissues reveals that each cell type has a unique sEV proteome. While classical sEV markers such as CD9/CD63/CD81 vary markedly in abundance, we identify six sEV markers (ENO1, GPI, HSPA5, YWHAB, CSF1R, and CNTN1) that are similarly abundant in sEVs of all cell types. In addition, each cell type has specific sEV markers. Using fat-specific Dicer-knockout mice with decreased white adipose tissue and increased brown adipose tissue, we show that these cell-type-specific markers can predict the changing origin of the serum sEVs. These results provide a valuable resource for understanding the sEV proteome of the cells and tissues important in metabolic homeostasis, identify unique sEV markers, and demonstrate how these markers can help in predicting the tissue of origin of serum sEVs.

Extracellular miRNAs as mediators of obesity-associated disease.

Extracellular miRNAs are found in a variety of body fluids and mediate intercellular and interorgan communication, thus regulating gene expression and cellular metabolism. These miRNAs are secreted either in small vesicles/exosomes (sEV) or bound to proteins such as Argonaute and high-density lipoprotein. Both exosomal and protein-bound circulating miRNAs are altered in obesity. Although all tissues can contribute to changes in circulating miRNAs, adipose tissue itself is an important source of these miRNAs, especially those in sEVs. These are derived from both adipocytes and macrophages and participate in crosstalk between these cells, as well as peripheral tissues, including liver, skeletal muscle and pancreas, whose function may be impaired in obesity. Changes in levels of circulating miRNAs have also been linked to the beneficial effects induced by weight loss interventions, including diet, exercise and bariatric surgery, further indicating a role for these miRNAs as mediators of disease pathogenesis. Here, we review the role of circulating miRNAs in the pathophysiology of obesity and explore their potential use as biomarkers and in therapy of obesity-associated metabolic syndrome.

Uso do teste de duplos esforços para avaliação da capacidade aeróbia de ratos obesos induzidos por dieta / Double effort test for evaluation of aerobic capacity of diet-induced obese rats

INTRODUÇÃO: Há uma grande carência na literatura de estudos aprofundando o conhecimento em relação às ações do lactato e algumas limitações nas investigações com indivíduos saudáveis ou portadores de algum transtorno metabólico. OBJETIVO: Verificar se é possível avaliar a capacidade aeróbia de ratos obesos induzidos por dieta através do teste de duplos esforços. MÉTODOS: Quatorze ratos machos Wistar foram divididos em dois grupos: Controle (Con) e Obeso (Obe). Os animais controles foram alimentados com ração-padrão e água fornecida ad libitum. O grupo de ratos obesos foi alimentado com ração padrão e dieta hiperlipídica. Após 12 semanas do início da dieta foi realizado o teste de tolerância à insulina, de máxima fase estável de lactato (MFEL) e o teste de duplos esforços. RESULTADOS: A dieta foi eficiente para induzir a obesidade nos animais. Os animais obesos apresentaram redução na sensibilidade à insulina de aproximadamente 19% (Con = 2,156 ± 0,1187 UA versus Obe = 1,742 ± 0,1551 UA). No teste de máxima fase estável, a concentração de lactato e velocidade correspondente ao limiar anaeróbio foram 3,780 ± 0,09 mmol/L e 18 m.min-1, para ambos os grupos. A velocidade de limiar estimada pelo teste de duplos esforços foi de 15,59 ± 0,653 m.min-1 para os animais controles e 14,02 ± 0,565 m.min-1 para os animais obesos. O teste de duplos esforços subestimou a capacidade aeróbia dos animais controles em 13% e obesos em 8,7%, contudo, apresentou correlação significativa com a MFEL (r = 0,88; P < 0,0075 Con / r = 0,92; P < 0,0031 Obe). CONCLUSÃO: O teste de duplos esforços pode ser uma alternativa interessante para avaliar a capacidade aeróbia tanto de animais sedentários saudáveis como de animais obesos.

INTRODUCTION: The literature lacks studies about lactate actions and some limitations in studies involving healthy individuals or patients with some metabolic disorder. OBJECTIVES: This study aimed to evaluate the protocol of double effort test for obese-induced rats. METHODS: Fourteen male Wistar rats were divided into two groups: Control (Con) and Obese (Obe). The control group was fed with standard chow and water ad libitum. The obese group was fed with standard chow, water ad libitum and hyperlipidic diet. Twelve weeks after the beginning of the hyperlipidic diet, insulin tolerance test, Maximal Lactate Steady State (MLSS) test and the double efforts test were performed. RESULTS: The diet was effective to promote obesity. The obese group decreased insulin sensitivity in approximately 19% (Con = 2.156 ± 0.1187 AU vs Obe = 1.742 ± 0.1551 AU). The lactate concentration and velocity of anaerobic threshold at MLSS test were 3.780 ± 0.09 mmol/L e 18 m.min-1 in both groups. The velocity of anaerobic threshold estimated by double efforts test was 15.59±0.653 m.min-1 in Con group control animals and 16.42±0.672 m.min-1 in Obe group. The double effort test underestimated around 13% and 8.7% the aerobic capacity in control and obese groups respectively, however, presented significant correlation with MLSS (r = 0,88; P < 0,0075 controls / r = 0,92; P < 0,0031 obese). CONCLUSION: So, the double effort test can be an interesting alternative to evaluate the aerobic capacity for both healthy sedentary and obese animals.

[Resistive training reduces inflammation in skeletal muscle and improves the peripheral insulin sensitivity in obese rats induced by hyperlipidic diet]. / Treinamento resistido reduz inflamação em músculo esquelético e melhora a sensibilidade à insulina periférica em ratos obesos induzidos por dieta hiperlipídica.

OBJECTIVE: To determine if resistive exercise protocol can modulate Tnf-α, SOCS3 and glucose transporter GLUT4 genes expression in skeletal muscle, and peripheral insulin sensitivity in obese rats induced by hyperlipidic diet. MATERIALS AND METHODS: Wistar obese rats induced by hyperlipidic diet were subjected a resistive exercise protocol as jump squat. Insulin sensitivity and mRNA content of Tnf-α, SOCS3 and GLUT4 were assayed and compared among the groups: obese sedentary (OS) and exercised (OE), control sedentary (CS) and exercised (CE). RESULTS: The mRNA content of Tnf-α and SOCS3 has increased in skeletal muscle from OS and has decreased in OE group. The protein and GLUT4 mRNA contents were correlated but they did not change among the groups. Peripheral insulin sensitivity has increased in the OE compared to OS group. CONCLUSION: The resistive exercise reverses the peripheral insulin resistance and the inflammatory state in skeletal muscle from diet-induced obese rats.

Treinamento resistido reduz inflamação em músculo esquelético e melhora a sensibilidade à insulina periférica em ratos obesos induzidos por dieta hiperlipídica / Resistive training reduces inflammation in skeletal muscle and improves the peripheral insulin sensitivity in obese rats induced by hyperlipidic diet

OBJETIVO: Investigar em ratos obesos o efeito da prática de exercício resistido sobre a sensibilidade à insulina e sobre a expressão de citocinas pró-inflamatórias e de transportador de glicose em músculo solear. MATERIAIS E MÉTODOS: Ratos Wistar alimentados com dieta hiperlipídica (grupos obesos) foram submetidos ao protocolo de exercício tipo jump squat. A sensibilidade à insulina e a expressão gênica de Tnf-α, SOCS3 e GLUT4 foram comparadas entre os grupos obesos sedentários (OS) e exercitados (OE) e controles sedentários (CS) e exercitados (CE). RESULTADOS: A sensibilidade à insulina estava reduzida no grupo OS e elevada no OE. Os conteúdos de RNAm de Tnf-α e de SOCS3 estavam aumentados no músculo esquelético do grupo OS e reduzidos no OE. O conteúdo proteico e de RNAm de GLUT4 não diferiu entre os grupos. CONCLUSÃO: O exercício resistido reverte o quadro de resistência à insulina periférica e de inflamação no músculo esquelético de obesos induzidos por dieta.

OBJECTIVE: To determine if resistive exercise protocol can modulate Tnf-α, SOCS3 and glucose transporter GLUT4 genes expression in skeletal muscle, and peripheral insulin sensitivity in obese rats induced by hyperlipidic diet. MATERIALS AND METHODS: Wistar obese rats induced by hyperlipidic diet were subjected a resistive exercise protocol as jump squat. Insulin sensitivity and mRNA content of Tnf-α, SOCS3 and GLUT4 were assayed and compared among the groups: obese sedentary (OS) and exercised (OE), control sedentary (CS) and exercised (CE). RESULTS: The mRNA content of Tnf-α and SOCS3 has increased in skeletal muscle from OS and has decreased in OE group. The protein and GLUT4 mRNA contents were correlated but they did not change among the groups. Peripheral insulin sensitivity has increased in the OE compared to OS group. CONCLUSION: The resistive exercise reverses the peripheral insulin resistance and the inflammatory state in skeletal muscle from diet-induced obese rats.