Cardiac Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase Causes Adverse Myocardial Remodeling following Myocardial Infarction

The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.     

Muscle hypertrophy and fast fiber type conversions in heavy resistance-trained women

Twenty-four women completed a 20-week heavy-resistance weight training program for the lower extremity. Workouts were twice a week and consisted of warm-up exercises followed by three sets each of full squats, vertical leg presses, leg extensions, and leg curls. All exercises were performed to failure using 6-8 RM (repetition maximum). Weight training caused a significant increase in maximal isotonic strength (1 RM) for each exercise. After training, there was a decrease in body fat percentage (p less than 0.05), and an increase in lean body mass (p less than 0.05) with no overall change in thigh girth. Biopsies were obtained before and after training from the superficial portion of the vastus lateralis muscle. Sections were prepared for histological and histochemical examination. Six fiber types (I, IC, IIC, IIA, IIAB, and IIB) were distinguished following routine myofibrillar adenosine triphosphatase histochemistry. Areas were determined for fiber types I, IIA, and IIAB + IIB. The heavy-resistance training resulted in significant hypertrophy of all three groups: I (15%), IIA (45%), and IIAB + IIB (57%). These data are similar to those in men and suggest considerable hypertrophy of all major fiber types is also possible in women if exercise intensity and duration are sufficient. In addition, the training resulted in a significant decrease in the percentage of IIB with a concomitant increase in IIA fibers, suggesting that strength training may lead to fiber conversions.     

The larval development of lateral musculature in gilthead sea bream Sparus aurata and sea bass Dicentrarchus labrax

Fibre-type differentiation of the lateral musculature has been studied in Sparus aurata (L.) and Dicentrarchus labrax (L.) during larval development. Histochemical and ultrastructural techniques show two presumptive muscle layers and two germinative zones of presumptive myoblasts. At hatching, myotomal muscle consists of a monolayer of thin undifferentiated cells near the skin (first germinative zone) overlying another mono-layer of small diameter fibres extending hypaxially and epaxially away from the transverse septum. Below this, there is a much thicker, deep layer of fibres, generally large in diameter and polygonal in shape. The presumptive myoblasts are located between these two layers of fibres in the second germinative zone. Initially, the superficial and deep muscle fibres show high and low myosin ATPase activity, respectively. Both layers grow by generating new fibres from the two mentioned germinative zones. At the end of larval life, the superficial layer changes its histochemical profile from high to low myosin ATPase activity and, at the same time, intermediate or pink muscle fibres can be observed by oxidative activity (the NADH-TR reaction). Morphometric analysis shows a significant increase in mean fibre diameter during successive ages, as shown by the Student's t-test (hypertrophic growth). Skewness and kurtosis values of fibre diameters point to the generation of a new fibre population from the germinative zones (hyperplastic growth).     

Características de los programas de entrenamiento de fuerza muscular en personas mayores con sarcopenia. Revisión de alcance

ObjectiveThe aim of this scoping review was to analyze the resistance training-based programs’ characteristics and outcomes of physical and psychological health and cognitive functions measured in older adults with sarcopenia.MethodThis scoping review was carried out following the criteria and flow diagram established in the PRISMA guidelines and included studies from 2011 until 2020 from electronic databases, including PubMed, Scopus, and Web of Science.ResultsA total of 13 randomized controlled trials were included. The sample's average age was 72.2 years, with an age range between 71 and 80 years, considering a total sample of 1029 older adults (57% women). Resistance training-based programs were carried out mainly in university facilities, presented high adherence (91.2%) and were able to induce increase in strength and muscle mass. The most frequent parameters used were 2-3 weekly, 50-90-min-long sessions for 3-9 months, using between 8 and 15 repetitions, in an intense training zone with 1-RM between 60% and 85%. The most measured physical health outcomes were muscle strength, muscle mass, and BMI. Cognitive impairment was frequently evaluated, and few studies evaluated mental health.ConclusionThis review characterized resistance training-based programs in older people with sarcopenia, highlighting the extension, frequency, duration, and intensity of these, as well the most frequently used outcome measures and instruments. These results could be useful for prescribing future resistance training-based programs in older adults with sarcopenia.     

Cardiomyopathy Mutations in the Tail of β-Cardiac Myosin Modify the Coiled-coil Structure and Affect Integration into Thick Filaments in Muscle Sarcomeres in Adult Cardiomyocytes

It is unclear why mutations in the filament-forming tail of myosin heavy chain (MHC) cause hypertrophic or dilated cardiomyopathy as these mutations should not directly affect contraction. To investigate this, we first investigated the impact of five hypertrophic cardiomyopathy-causing (N1327K, E1356K, R1382W, E1555K, and R1768K) and one dilated cardiomyopathy-causing (R1500W) tail mutations on their ability to incorporate into muscle sarcomeres in vivo. We used adenoviral delivery to express full-length wild type or mutant enhanced GFP-MHC in isolated adult cardiomyocytes. Three mutations (N1327K, E1356K, and E1555K) reduced enhanced GFP-MHC incorporation into muscle sarcomeres, whereas the remainder had no effect. No mutations significantly affected contraction. Fluorescence recovery after photobleaching showed that fluorescence recovery for the mutation that incorporated least well (N1327K) was significantly faster than that of WT with half-times of 25.1 ± 1.8 and 32.2 ± 2.5 min (mean ± S.E.), respectively. Next, we determined the effects of each mutation on the helical properties of wild type and seven mutant peptides (7, 11, or 15 heptads long) from the myosin tail by circular dichroism. R1382W and E1768K slightly increased the α-helical nature of peptides. The remaining mutations reduced α-helical content, with N1327K showing the greatest reduction. Only peptides containing residues 1301–1329 were highly α-helical suggesting that this region helps in initiation of coiled coil. These results suggest that small effects of mutations on helicity translate into a reduced ability to incorporate into sarcomeres, which may elicit compensatory hypertrophy.     

FOG2 Protein Down-regulation by Transforming Growth Factor-β1-induced MicroRNA-200b/c Leads to Akt Kinase Activation and Glomerular Mesangial Hypertrophy Related to Diabetic Nephropathy

Glomerular hypertrophy is a hallmark of diabetic nephropathy. Akt kinase activated by transforming growth factor-β1 (TGF-β) plays an important role in glomerular mesangial hypertrophy. However, the mechanisms of Akt activation by TGF-β are not fully understood. Recently, miR-200 and its target FOG2 were reported to regulate the activity of phosphatidylinositol 3-kinase (the upstream activator of Akt) in insulin signaling. Here, we show that TGF-β activates Akt in glomerular mesangial cells by inducing miR-200b and miR-200c, both of which target FOG2, an inhibitor of phosphatidylinositol 3-kinase activation. FOG2 expression was reduced in the glomeruli of diabetic mice as well as TGF-β-treated mouse mesangial cells (MMC). FOG2 knockdown by siRNAs in MMC activated Akt and increased the protein content/cell ratio suggesting hypertrophy. A significant increase of miR-200b/c levels was detected in diabetic mouse glomeruli and TGF-β-treated MMC. Transfection of MMC with miR-200b/c mimics significantly decreased the expression of FOG2. Conversely, miR-200b/c inhibitors attenuated TGF-β-induced decrease in FOG2 expression. Furthermore, miR-200b/c mimics increased the protein content/cell ratio, whereas miR-200b/c inhibitors abrogated the TGF-β-induced increase in protein content/cell. In addition, down-regulation of FOG2 by miR-200b/c could activate not only Akt but also ERK, which was also through PI3K activation. These data suggest a new mechanism for TGF-β-induced Akt activation through FOG2 down-regulation by miR-200b/c, which can lead to glomerular mesangial hypertrophy in the progression of diabetic nephropathy.     

Effects of jaw adductor hypertrophy on buccal expansions during feeding of air breathing catfishes (Teleostei,Clariidae)

Some species of Clariidae (air breathing catfishes) have extremely well developed (hypertrophied) jaw closing muscles that increase the maximal biting force of these species. As these enlarged jaw muscles tightly cover the suspensoria, which are firmly connected to the neurocranium, we expect diminished lateral expansions during suction for species with hypertrophied jaw muscles. In turn, this could imply a reduced suction performance for these species. Compared to Clarias gariepinus, which has relatively small jaw closers, Clariallabes longicauda shows a clear hypertrophy of the jaw adductors. A kinematic analysis of prey capture in these two species is presented here. As predicted, Clariallabes longicauda shows less lateral expansion (average abduction of the hyoids of 19.0°) than Clarias gariepinus (abduction of 31.1°). However, our data indicate that the decrease in lateral expansion capacity in the species with excessive adductor development is compensated for by a larger and faster ventral expansion of the buccal cavity by depression of the hyoid.     

Forskolin fails to activate L-type calcium current in hypertrophied cardiomyocytes of chronically hypoxic rats

We have shown that the contractile, cytosolic calcium ([Ca2+]i) and cyclic AMP (cAMP) responses to beta-adrenoceptor stimulation are attenuated in ventricular myocytes of chronically hypoxic (CH) rats. The aim of this study was to examine the effect of forskolin on the L-type Ca2+ current in CH hypertrophied ventricular myocytes. Patch-clamp recording of the L-type Ca2+ current was measured in right ventricular myocytes of normoxic control and CH rats exposed to 10% inspired oxygen for 4 weeks. The breadth, but not the length, of CH myocytes was significantly greater than that of the control group. Activation of beta-adrenoceptor with isoproterenol (0.1 microM) increased the peak Ca2+ current by 83% in the normoxic control but the increase of peak Ca2+ current was not significant in the CH myocytes. Forskolin (0.1 - 1 microM), an activator of adenylyl cyclase, increased the peak Ca2+ current by 49% - 102% in the normoxic controls but it did not cause significant change of the peak Ca2+ current in CH myocytes. These results suggest an absence of forskolin-induced activation of Ca2+ current in hypertrophied ventricular myocytes during chronic hypoxia. The failure of activation of the Ca2+ current is consistent with the idea that adenylyl cyclase function is down-regulated in CH hypertrophied myocytes.     

Integrin-linked kinase is a central mediator in angiotensin II type 1- and chemokine receptor CXCR4 signaling in myocardial hypertrophy

Inflammation and pro-hypertrophic signaling are important for development and progression of myocardial hypertrophy (LVH) and chronic heart failure (CHF). Here we investigated the relevance of integrin-linked kinase (ILK) for chemokine receptor CXCR4- and angiotensin II type 1-triggered signaling and its regulation and role in cardiac remodeling.Using ELISA, real-time-PCR, and Western blotting, the present study demonstrates that SDF-1 and its receptor CXCR4 are up-regulated in plasma and left ventricles, respectively, in mouse models of cardiac hypertrophy (transaortic constriction, transgenic cardiac-specific overexpression of rac1) and in human CHF in association with increased cardiac ILK-expression. In isolated cardiomyocytes, ILK is activated by CXCR4-ligation and necessary for SDF-1-triggered activation of rac1, NAD(P)H oxidase, and release of reactive oxygen species. Importantly, the pro-hypertrophic peptide angiotensin II induces ILK-activation dependent on rac1 in cardiomyocytes, where ILK is necessary for angiotensin II-mediated stimulation of hypertrophy genes and protein synthesis.We conclude that in both SDF-1- and angiotensin II-triggered signaling, ILK is a central mediator of rac1-induced oxidative stress and myocardial hypertrophy.