👤 Sagar Vyavahare

Muscle wasting can be caused by nutrition deficiency and inefficient metabolism of amino acids, including Branched Chain Amino Acids (BCAAs). Branched Chain Amino Acids are a major contributor to the metabolic needs of healthy muscle and account for over a tenth of lean muscle mass. Branched chain alpha-ketoacid dehydrogenase (BCKD) is the rate limiting enzyme of BCAA metabolism. Inhibition of BCKD is achieved through a reversible phosphorylation event by Branched Chain a-ketoacid dehydrogenase kinase (BCKDK). Our study set out to determine the importance of BCKDK in the maintenance of skeletal muscle. We used the Gene Expression Omnibus Database to understand the role of BCKDK in skeletal muscle pathogenesis, including aging, muscular disease, and interrupted muscle metabolism. We found BCKDK expression levels were consistently decreased in pathologic conditions. These results were most consistent when exploring muscular disease followed by aging. Based on our findings, we hypothesize that decreased BCKDK expression alters BCAA catabolism and impacts loss of normal muscle integrity and function. Further research could offer valuable insights into potential therapeutic strategies for addressing muscle-related disorders. Show less

An Abdominal aortic aneurysm (AAA), a deadly disease in elderly population, is featured by expansion of aortic diameter, degradation and weakening of vasculature. Its common and significant characteristics are disarray and inflammation in vasculature. We tested the hypothesis that the reversal of abdominal aortic aneurysm by pentagalloyl glucose-loaded nanoparticles (PGG-NPs) therapy that targets degraded elastin suppresses inflammatory and immune markers to ameliorate the pathophysiology of the disease in advance stage aneurysm in a porcine pancreatic elastase (PPE)-induced mouse model of AAA. After induction of aneurysm in pathogen-free C57BL/6 male mice by applying PPE peri-adventitially to the abdominal aorta, once a week for two doses of intravenous injections of pentagalloyl glucose-loaded nanoparticles (PGG-NPs) conjugated with elastin targeted antibody were used to reverse the aneurysms. We showed that PGG-NPs therapy could suppress infiltration of macrophages, CD8 and CD4 subsets of T cells, matrix metalloproteinases (MMPs), inflammatory cytokines interferon (IFN-γ) and interleukin (IL)-6 at the local and systemic level. Moreover, such PGG-NPs therapy increases the induction of anti-inflammatory cytokines IL-13, IL-27 and IL-10 at the local and systemic level. The therapy also led to remodeling of elastic lamina at the aneurysm site. Nanoparticles-loaded pentagalloyl glucose therapy can be an effective treatment option against advanced stage aneurysms to reverse the disease by ameliorating inflammation and restoring arterial homeostasis. Show less

Receptors to glucose-dependent insulinotropic polypeptide (GIP), have been identified on bone and GIP receptor (GIPr) knockout mice exhibit reduced bone strength and quality. Despite this, little is known on the potential beneficial bone effects of exogenous GIP on bone physiology. The aim of the present study was to assess whether stable GIP analogues were capable of ameliorating bone strength in mice with diet-induced obesity. The stable GIP analogue (D-Ala²)-GIP, and (D-Ala²)-GIP-Tag, a specific GIP analogue homing exclusively to bone, were employed. In vitro studies were used to assess effects of (D-Ala²)-GIP and (D-Ala²)-GIP-Tag on bone mineralization, lysyl oxidase activity, collagen maturity as well as osteoclast formation and activity. Subsequent in vivo studies employed obese-prediabetic Swiss NIH mice subjected to a 42-day period of daily administration of saline, (D-Ala²)-GIP or (D-Ala²)-GIP-Tag. In vitro studies confirmed that (D-Ala²)-GIP and (D-Ala²)-GIP-Tag had similar beneficial biological effects on bone cells. Administration of (D-Ala²)-GIP and (D-Ala²)-GIP-Tag resulted in lower blood glucose levels without any effects on body weight. Both GIP analogues augmented bone strength to a similar extent. Trabecular or cortical bone microarchitecture were not changed over the time course of the study. However, (D-Ala²)-GIP and (D-Ala²)-GIP-Tag augmented enzymatic collagen crosslinking as well as the heterogeneity of enzymatic collagen crosslinking, mineral-to-matrix ratio and significantly reduced the heterogeneity in mineral bone crystallite size. This study demonstrates that activation of skeletal GIPr by stable GIP analogues enhance bone strength in prediabetes and suggest that these analogues may be beneficial in the treatment of bone disease. Show less