Enhanced Muscle Strength in Dyslipidemic Mice and Its Relation to Increased Capacity for Fatty Acid Oxidation.

Dyslipidemia is commonly linked to skeletal muscle dysfunction, accumulation of intramyocellular lipids, and insulin resistance. However, our previous research indicated that dyslipidemia in apolipoprotein E and low-density lipoprotein receptor double knock-out mice (ApoE/LDLR -/-) leads to improvement of exercise capacity. This study aimed to investigate in detail skeletal muscle function and metabolism in these dyslipidemic mice. We found that ApoE/LDLR -/- mice showed an increased grip strength as well as increased troponins, and Mhc2 levels in skeletal muscle. It was accompanied by the increased skeletal muscle mitochondria numbers (judged by increased citrate synthase activity) and elevated total adenine nucleotides pool. We noted increased triglycerides contents in skeletal muscles and increased serum free fatty acids (FFA) levels in ApoE/LDLR -/- mice. Importantly, Ranolazine mediated inhibition of FFA oxidation in ApoE/LDLR -/- mice led to the reduction of exercise capacity and total adenine nucleotides pool. Thus, this study demonstrated that increased capacity for fatty acid oxidation, an adaptive response to dyslipidemia leads to improved cellular energetics that translates to increased skeletal muscle strength and contributes to increased exercise capacity in ApoE/LDLR -/- mice.

Chain-length dependent effects of inorganic polyphosphate on endothelial function and nucleotide pool.

Endothelial cells (ECs) are the first line that comes into contact with blood pathogens, pathogen-derived molecules, and factors that stimulate coagulation and inflammation. Inorganic polyphosphate (polyP) - a polymer of orthophosphate units synthesized by bacteria under stress and released by platelets upon their activation is among these factors. Bacterial and platelet polyPs differ in length, and both variants elicit different effects in eukaryotes. This study aimed to investigate how bacterial-like long-chain polyP (Lc-polyP) and platelet-like short-chain polyP (Sc-polyP) affect the functionality of cultured endothelial cells. Murine immortalized heart endothelial cells (H5V) were exposed to polyP of different chain lengths to assess the effects of these stimuli on intracellular energetics, permeability, and endothelial adhesion. We observed varying effects between Lc-polyP and Sc-polyP treatments. Lc-polyP more potently disturbs the intracellular ATP pool, a parameter strongly connected with vascular injury, whereas Sc-polyP robustly stimulates cellular adhesion to the endothelium. Both polymers similarly enhance endothelial permeability, suggesting potent immunomodulatory properties. This study provides evidence that polyP elicits profound cellular responses in endothelium depending on the polymer's length.

Fibroblast-derived matrix models desmoplastic properties and forms a prognostic signature in cancer progression.

The desmoplastic reaction observed in many cancers is a hallmark of disease progression and prognosis, particularly in breast and pancreatic cancer. Stromal-derived extracellular matrix (ECM) is significantly altered in desmoplasia, and as such plays a critical role in driving cancer progression. Using fibroblast-derived matrices (FDMs), we show that cancer cells have increased growth on cancer associated FDMs, when compared to FDMs derived from non-malignant tissue (normal) fibroblasts. We assess the changes in ECM characteristics from normal to cancer-associated stroma at the primary tumor site. Compositional, structural, and mechanical analyses reveal significant differences, with an increase in abundance of core ECM proteins, coupled with an increase in stiffness and density in cancer-associated FDMs. From compositional changes of FDM, we derived a 36-ECM protein signature, which we show matches in large part with the changes in pancreatic ductal adenocarcinoma (PDAC) tumor and metastases progression. Additionally, this signature also matches at the transcriptomic level in multiple cancer types in patients, prognostic of their survival. Together, our results show relevance of FDMs for cancer modelling and identification of desmoplastic ECM components for further mechanistic studies.

Inorganic Polyphosphate-Regulator of Cellular Metabolism in Homeostasis and Disease.

Inorganic polyphosphate (polyP), a simple anionic polymer consisting of even hundreds of orthophosphate units, is a universal molecule present in both simple and complex organisms. PolyP controls homeostatic processes in animals, such as blood coagulation, tissue regeneration, and energy metabolism. Furthermore, this polymer is a potent regulator of inflammation and influences host immune response in bacterial and viral infections. Disturbed polyP systems have been related to several pathological conditions, including neurodegeneration, cardiovascular disorders, and cancer, but we lack a full understanding of polyP biogenesis and mechanistic insights into the pathways through which polyP may act. This review summarizes recent studies that describe the role of polyP in cell homeostasis and show how disturbances in polyP levels may lead to disease. Based on the collected findings, we highlight the possible usage of this polymer as a promising therapeutic tool in multiple pathologies.