Biology subjects

Dymkowska, D.

Publications and source records attributed to Dymkowska, D..

3 recordsLinked to original sources

bioRxiv2025

Unconventional myosin VI is involved in the regulation of muscle energy metabolism

Mitochondria are essential for regulation of the metabolic state of skeletal muscle, making their structure and function crucial for muscle performance. Myosin VI (MVI), an unconventional minus-end-directed motor, is expressed in skeletal muscle and myogenic cells. To explore its role in mitochondrial function and muscle metabolism, we used MVI knockout mice (Snells waltzer, SV) and their heterozygous littermates. We analyzed muscle samples from newborn (P0) and adult mice (3- and 12-month-old) and found that both MVI mRNA and protein levels were highest in newborn muscles and decreased with age. MVI expression also varied by muscle type, being highest in the slow-twitch soleus muscle (SOL) of adult mice. Loss of MVI had the most significant effects on SOL, which contains the highest number of mitochondria compared to fast-twitch muscles. MVI loss resulted in reduced respiratory capacity and ATP production in myogenic cells, indicating impaired mitochondrial function. Furthermore, MVI deficiency caused a shift from glycolytic to oxidative fiber types, especially in SOL. We also observed increased phospho-AMPK levels in MVI-KO SOL across all time points, along with downregulation of the mTOR pathway and upregulation of proteins involved in lipolysis. These findings highlight MVI as a novel regulator of metabolic processes in skeletal muscle.

physiology↗

bioRxiv2024

Chitinase-1 inhibition reverses metabolic dysregulation and restores homeostasis in MASH animal models

OATD-01 is a chitinase-1 (CHIT1) inhibitor, reducing inflammation and fibrosis in animal models where chronic inflammation leads to tissue remodeling. CHIT1, predominantly secreted by macrophages, is overexpressed in metabolic-dysfunction-associated steatohepatitis (MASH). In this study, we demonstrated the efficacy of OATD-01 in two murine and a rat model of MASH. RNA-Seq analysis revealed that OATD-01 reversed MASH-dysregulated genes. Apart from the attenuation of inflammation and fibrosis, OATD-01 regulated metabolic processes such as lipid metabolism and glycolysis. We demonstrated that both genetic and pharmacological inactivation of CHIT1 resulted in inhibition of glycolysis and glucose uptake in primary macrophages. As a consequence, we observed increased ATP, lower citrate and increased acetate levels, resulting in a reduced IL-1{beta} secretion. These results revealed the key role for CHIT1 in regulating metabolism. OATD-01 is a macrophage modulator that can directly restore metabolic balance and consequently inhibit inflammation and fibrosis, supporting its use for MASH treatment.

pharmacology and toxicology↗

bioRxiv2021

Effect of lipopolysaccharide (LPS) on HAEC cells. Does nicotinamide N-methyltranferase sensitize HAEC cells to LPS?

Treatment of endothelial cells with bacterial lipopolysaccharide (LPS) evokes a number of metabolic and functional consequences which built a multifaceted physiological response of endothelium to bacterial infection. Here effects of LPS on human aortic endothelial cells (HAEC) have been investigated. Among the spectrum of biochemical changes substantially elevated N-nicotinamide methyltransferase (NNMT) protein level was particularly intriguing. This important enzyme may potentially affect cellular metabolism by two means: direct regulation of methylnicotinamide level and availability of nicotinamide, that at least potentially may influence NAD+ synthesis, and regulation of S-adenosylmethionine concentration and therefore controlling methylation of many proteins including chromatin. This may have epigenetic consequences. This paper is focused on NNMT, despite the fact that in the presence of LPS additional effects of this compound mask pure (canonical) consequences of the elevated NNMT protein which are an increased MNA synthesis or reduced NAD+ level. On the other hand, however, it has been shown that silencing of the NNMT-encoding gene prevents several changes which are observed in control HAECs treated with LPS. They include significantly increased calcium response to thapsigargin (store-operated calcium entry), altered energy metabolism which is switched to anaerobic glycolysis and rearrangement of the mitochondrial network. However, a biochemical mechanism behind the protective consequences of the NNMT deficiency in cells treated with LPS remains unexplained.

biochemistry↗