In Vitro Degradation Behavior and Biocompatibility of Bioresorbable Molybdenum

The degradation behavior and biocompatibility of pure molybdenum (Mo) were investigated. Dissolution of powder metallurgically manufactured and commercially available Mo was investigated by ion concentration measurement after immersion in modified Kokubo’s SBF (c-SBF-Ca) for 28 days at 37 °C and pH 7.4. Degradation layers and corrosion attack were examined with optical microscopy and REM/EDX analysis. Furthermore, potentiodynamic polarization measurements were conducted. Mo gradually dissolves in modified SBF releasing molybdate anions (MoO42−). The dissolution rate after 28 days is 10 µm/y for both materials and dissolution accelerates over time. A non-passivating, uniform and slowly soluble degradation product layer is observed. Additionally, apoptosis and necrosis assays with Mo ion extracts and colonization tests with human endothelial (HCAEC) and smooth muscle cell lines (HCASMC) on Mo substrates were performed. No adverse effects on cell viability were observed for concentrations expected from the dissolution of implants with typical geometries and substrates were densely colonized by both cell lines. Furthermore, Mo does not trigger thrombogenic or inflammatory responses. In combination with its favorable mechanical properties and the renal excretion of bio-available molybdate ions, Mo may be an alternative to established bioresorbable metals

Biodegradation and biocompatibility of molybdenum as an implant material

Biodegradable metals have entered the implant market in recent years, but still do not show fully satisfactory degradation behaviour and mechanical properties. In contrast, it has been shown that pure molybdenum has an excellent combination of the required properties in this respect. We report on PM based screen printing of thin-walled molybdenum tubes as a processing step for medical stent manufacture. We also present data on the in vivo degradation and biocompatibility of molybdenum. The degradation of molybdenum wires implanted in the aorta of rats was evaluated by SEM and EDX. Biocompatibility was assessed by histological investigation of organs and analysis of molybdenum levels in tissue extracts and body fluids. Degradation rates of up to 13.5 μm/y were observed after 12 months. No histological changes or elevated molybdenum levels in organ tissues were observed. In summary, the results further underline that molybdenum is a highly promising biodegradable metallic material

Empagliflozin Preserves Skeletal Muscle Function in a HFpEF Rat Model

Besides structural alterations in the myocardium, heart failure with preserved ejection fraction (HFpEF) is also associated with molecular and physiological alterations of the peripheral skeletal muscles (SKM) contributing to exercise intolerance often seen in HFpEF patients. Recently, the use of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) in clinical studies provided evidence for a significant reduction in the combined risk of cardiovascular death or hospitalization for HFpEF. The present study aimed to further elucidate the impact of Empagliflozin (Empa) on: (1) SKM function and metabolism and (2) mitochondrial function in an established HFpEF rat model. At the age of 24 weeks, obese ZSF1 rats were randomized either receiving standard care or Empa in the drinking water. ZSF1 lean animals served as healthy controls. After 8 weeks of treatment, echocardiography and SKM contractility were performed. Mitochondrial function was assessed in saponin skinned fibers and SKM tissue was snap frozen for molecular analyses. HFpEF was evident in the obese animals when compared to lean—increased E/é and preserved left ventricular ejection fraction. Empa treatment significantly improved E/é and resulted in improved SKM contractility with reduced intramuscular lipid content. Better mitochondrial function (mainly in complex IV) with only minor modulation of atrophy-related proteins was seen after Empa treatment. The results clearly documented a beneficial effect of Empa on SKM function in the present HFpEF model. These effects were accompanied by positive effects on mitochondrial function possibly modulating SKM function

Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility

Background About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed-205) in HFpEF and to describe molecular changes elicited by MyoMed-205. - Methods Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (healthy) and obese rats as controls. LV (left ventricle) unction was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity. - Results By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e′ ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1. - Conclusions MyoMed-205 improved myocardial diastolic function and prevented SKM atrophy/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis