Biology subjects

Mustafa, T.

Publications and source records attributed to Mustafa, T..

5 recordsLinked to original sources

bioRxiv2025

α-Melanocyte Stimulating Hormone Reduces Blood Glucose Across Species

Peripheral administration of -melanocyte stimulating hormone (-MSH) promotes glucose uptake in skeletal muscle via a melanocortin 5 receptor (MC5R)-dependent mechanism in rodents. Here we demonstrate that this pathway is functional in humans. During an oral glucose tolerance test (GTT) in healthy human volunteers, peripheral administration of -MSH was well tolerated, and reduced glucose and insulin incremental area under the curve by 39% and 35%, respectively. During a GTT in non-human primates, both -MSH and a selective MC5R agonist, PG-901, increased glucose tolerance. In vitro, both -MSH and PG-901 induced glucose uptake in primary human and non-human primate myotubes and immortalised human myotubes. Subcutaneous injection of PG-901 reduced blood glucose concentrations during a GTT in WT mice but had no effect in MC5R deficient mice. Thus, the novel MC5R-skeletal muscle pathway found in animals is functional in humans and represents a novel target for glycaemic control in people with diabetes.

physiology↗

bioRxiv2025

Hypoxia modulates human pulmonary arterial adventitial fibroblast phenotype through HIF-1α activation

Hypoxic pulmonary hypertension (HPH) develops in association with diseases characterized by low oxygen levels leading to pulmonary artery (PA) narrowing and death. Hypoxia has been linked to increased PA collagen and changes in PA adventitial fibroblast (PAAF) metabolism. However, the mechanisms by which hypoxia regulates PAAF function are unknown. Hypoxia-inducible factor-1 (HIF-1) is a subunit of a transcription factor that is degraded in normoxia but stabilized in hypoxia and is involved in extracellular matrix remodeling by fibroblasts. We examined the role of hypoxia and HIF-1 in regulating PAAF function. Human PAAF (HPAAF) were cultured in normoxic and hypoxic conditions. Cells were further treated with HIF1- inhibitor or no drug. Protein expression, mRNA expression, enzyme activity, and metabolite concentration were examined. Male C57BL6/J mice were exposed to 0 or 10 days of hypoxia after which right ventricular hemodynamics and tissue metabolism were assessed. Hypoxia led to an increase in collagen content and decrease in matrix metalloproteinase-2 (MMP2) activity. HIF-1 inhibition limited collagen accumulation and restored MMP2 activity. HPAAF demonstrated elevated lactic acid concentration and decreased ATP in hypoxia. HIF-1 inhibition blunted these effects. Mice exposed to hypoxia developed significant elevation in right ventricle systolic pressures and had decreased ATP levels in pulmonary tissue. This study investigated the mechanisms by which hypoxia drives HPAAF-mediated collagen accumulation and metabolic changes. We identify the key role of HIF-1 in regulating changes. These findings provide important insights into understanding HPAAF-mediated PA remodeling and help identify possible novel therapeutic targets.

bioengineering↗

bioRxiv2024

ACTN3 genotype influences androgen response in skeletal muscle

AbstractAndrogens are vital for the maintenance of muscle mass and their anabolic effects are primarily exerted through the androgen receptor (AR). Accumulating evidence in humans and mice suggests that circulating androgens, AR and androgen response are influenced by ACTN3 (- actinin-3), also known as "the gene for speed". One in 5 people worldwide are -actinin-3 deficient due to homozygous inheritance of a common null polymorphism (577X) in ACTN3. In this study, we show that -actinin-3 deficiency decreases baseline AR in skeletal muscles of mice and humans, in both males and females, and that AR expression directly correlates with ACTN3 in a dosage dependent manner. We further demonstrate in Actn3 knockout mice that - actinin-3 deficiency increases muscle wasting induced by androgen deprivation and reduces the muscle hypertrophic response to dihydrotestosterone and this is mediated by differential activation of pathways regulating amino acid metabolism, intracellular transport, MAPK signalling, autophagy, mitochondrial activity and calcineurin signalling. Gene set enrichment and protein analyses indicate that the absence of -actinin-3 results in a failure to coactivate many of these pathways in response to changes in androgens, and relies on leveraging mitochondrial remodelling and calcineurin signalling to restore muscle homeostasis. We further identified 7 genes that are androgen sensitive and -actinin-3-dependent in expression, and whose functions correspond to these processes. Our results highlight the pivotal role of - actinin-3 in various processes associated with the regulation of protein turnover and muscle mass, and suggest that ACTN3 genotype is a genetic modifier of androgen action in skeletal muscle.

genetics↗

bioRxiv2022

Application of Physiological and Pathological Wall Shear Stress to Endocardial Endothelial Cells Triggers Complex Signaling Pathways

Discrete subaortic stenosis (DSS) is a congenital heart disease in which a fibrotic membrane forms below the aortic valve; the underlying cellular mechanisms are currently unknown. Since an elevated pressure gradient in the left ventricular outflow tract (LVOT) is a distinguishing feature of DSS, it is hypothesized that the membrane formation is caused by elevated wall shear stress applied to the endocardial endothelial cells (EECs) that line the LVOT, triggering fibrosis. To correlate shear stress to an EEC fibrotic phenotype, we applied fluid shear stress to EECs at physiological and pathological shear rates using a cone-and-plate device, designed to recapitulate physiological wall shear stress in a controlled in vitro environment. Controlled shear stress regimes were applied to EECs to replicate the conditions observed in DSS patients. We found that elevated shear stress triggered EEC alignment as well as endothelial-to-mesenchymal transformation (EndMT) signaling pathways driven by upregulation of SNAI1 gene expression. The EECs were then treated with a small molecule inhibitor of Snail1 protein, CYD19, to attempt to attenuate EndMT signaling, and subsequently subjected to pathological shear stress. The Snail1 inhibitor did downregulate selected markers of EndMT signaling, although only transiently. Interestingly, the application of shear stress had a greater effect on the EEC gene and protein expression than did the Snail1 inhibition. This investigation of EEC response to shear stress reveals the pronounced and complex effect of this mechanical stimulation on the EEC phenotype. Further study should reveal the mechanisms that drive fibrosis and the formation of the DSS membrane.

bioengineering↗

bioRxiv2022

Increasing computational protein design literacy through cohort-based learning for undergraduate students

Undergraduate research experiences can improve student success in graduate education and STEM careers. During the COVID-19 pandemic, undergraduate researchers at our institution and many others lost their work-study research positions due to interruption of in-person research activities. This imposed a financial burden on the students and eliminated an important learning opportunity. To address these challenges, we created a paid, fully-remote, cohort-based research curriculum in computational protein design. Our curriculum used existing protein design methods as a platform to first educate and train undergraduate students and then to test research hypotheses. In the first phase, students learned computational methods to assess the stability of designed protein assemblies. In the second phase, students used a larger dataset to identify factors that could improve the accuracy of current protein design algorithms. This cohort-based program created valuable new research opportunities for undergraduates at our institute and enhanced the undergraduates feeling of connection with the lab. Students learned transferable and useful skills such as literature review, programming basics, data analysis, hypothesis testing, and scientific communication. Our program provides a model of structured computational research training opportunities for undergraduate researchers in any field for organizations looking to expand educational access. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

scientific communication and education↗