Biology subjects

Parvatiyar, M. S.

Publications and source records attributed to Parvatiyar, M. S..

4 recordsLinked to original sources

bioRxiv2024

Evaluating the Sex Dependent Influence of Sarcospan on Cardiometabolic Disease Traits in Mice

Numerous genes including sarcospan (SSPN) have been designated as obesity-susceptibility genes by human genome-wide association studies. Variants in the sarcospan (SSPN) gene locus have been associated with obesity traits with a stronger effect in women. To date this association has not been tested in vivo, therefore, we assessed the susceptibility of young (2 month) global SSPN-deficient (SSPN-/-) mice to diet-induced obesity by feeding them high fat diet (HFD) or control diet (CD) for 16 weeks. Anthropometric measurements were used to assess outcomes to the diets including weight change, glucose handling, fat distribution, adipocyte size and effects on cardiac function. To assess the age-dependent impact of SSPN deletion we also compared the response of (13 month) male and female mice to HFD, which were aged by study completion. SSPN deficiency offered modest protection from weight gain in all groups studied, which was not attributable to reduced food consumption. Aging revealed glucose intolerance for SSPN-/- CD mice, which was significant in females. Young female mice had low % Fat and less visceral adipose tissue accumulation that remained relatively unchanged in HFD groups. However, this protection was lost with aging. SSPN-/- mice did not exhibit decrements in cardiac function in response to HFD. However, aged male SSPN-/- CD mice had significantly increased left ventricular mass (LVM) and signs of ventricular remodeling in response to HFD. These studies suggest that SSPN influences phenotype in a sex dependent manner and participates in a network of metabolic genes. New & NoteworthyIn this study the association of the sarcospan protein with human obesity is assessed using in vivo models. Sarcospan-deficient mice of both sexes show an age- dependent influence on adipose tissue biology and glucose handling in response to control and high fat diet. The effect of sarcospan deletion was more pronounced effects in females. Aging reveals susceptibility of SSPN-deficient male mice to increased left ventricular mass.

physiology↗

bioRxiv2024

Assessing a Role for Sarcospan in Immune Function

Sarcospan (SSPN) is a tetraspanin-like member of the dystrophin-glycoprotein complex (DGC) with expression reported at the transcript level in B cells and several other immune cell populations. SSPN is best known for its expression in skeletal, cardiac, and vascular smooth muscle, however it is expressed in other cell types and its roles in non-muscle cells have not been well described. Analysis of functional interactions of SSPN with effectors of hematopoietic cell lineages uncovered strong associations with several proteins with known roles in hematopoiesis and immune response. In this study, we utilized flow cytometry to uncover SSPN+ immune cell populations expressing the SSPN protein. We performed immunophenotyping of global SSPN-deficient (SSPN-/-) C57BL/6J male and female mice to assess whether SSPN plays an essential role in generation of specific immune cells. By flow cytometry we found that B cells, CD11b+ and CD11c+ (monocytes, tissue macrophages, and a subset of dendritic cells) express the highest levels of SSPN at their cell membranes. To pinpoint potential roles for SSPN in B cell development, SSPN-/- bone marrow cells were isolated and differentiated using phorbol myristate acetate (PMA). To test B cell effector functions, antibody isotype analysis was performed to assess whether SSPN influences antibody class switching. Blood serum of WT and SSPN-/- mice were tested for presence of important developmental signals for B cell maturation, development and isotype switching. Our study is the first to document SSPN protein expression on distinct classes of immune cells including CD11b+, CD11c+ and B cells (CD19+). Immunophenotyping revealed several differences in immune cell populations in the murine spleens: 1) a significant increase in % T cells in SSPN-/- males, 2) slight reduction of % B cells in SSPN-/- females, 3) a significant increase % of dendritic cells in SSPN-/- females, and 4) no significant alterations in NK cells. Under unstimulated conditions, SSPN-/- female mice had a significantly lower IgG2b titers compared to WT. Overall, the observation of SSPN expression in distinct immune cells, potential role(s) in hematopoiesis and B cell effector function is intriguing and warrants further investigation. HighlightsThe sarcospan protein has an established role in stabilization of striated muscle membranes and is an essential member of the dystrophin-glycoprotein complex. This study investigates the reported presence of Sspn in B cells and examines potential roles in immune function including: O_LIDetermining a connection with hematopoiesis and establishment of niches C_LIO_LIImpact on immune content in spleens of sarcospan-deficient mice C_LIO_LIIdentifying a role in B cell effector functions C_LI

immunology↗

bioRxiv2024

The Role of Sex in the Effects of Smoking and Nicotine in Cardiovascular Function, Atherosclerosis, and Inflammation

cigarette smoke (CS) invokes an inflammatory response involving increased levels of circulating cytokines and chemokines, vascular dysfunction, and atherosclerosis. The role of sex and nicotine in CS effects in cardiovascular function and atherosclerosis is unexplored. To assess the role of sex, male and female C57Bl/6 WT (wild type) and ApoE-/- mice were exposed to CS and nicotine for 16 weeks to bridge this literature gap. Heart rate and endothelial function were measured in the aorta of WT mice, while plasma levels of lipids, cytokines and chemokines and aortic plaque burden was assessed in ApoE-/- mice. CS increased heart rate to similar levels in both sexes and induced a stronger impairment in endothelial function in males and more plaque in females than nicotine. Females showed a higher necrotic core area at basal compared with males, while males had a higher calcification area than females by CS. Senescence-associated GLB1/-galactosidase (SA-GLB1) activity was elevated similarly in both sexes by both treatments. Total cholesterol (TC) was elevated by CS in both sexes. CS increased triglycerides (TG), very-low density lipoprotein (VLDL) and high-density lipoprotein (HDL) only in males and low-density lipoprotein (LDL) only in females. Interleukin 17A (IL17A) was upregulated by CS and nicotine in both sexes, while CS upregulated C-X-C motif chemokine ligand 5 (CXCL5/LIX) and interleukin 1 alpha (IL1A) in males and females, respectively. Additionally, nicotine metabolism showed sex specific responses to nicotine, but not smoking. Overall, we identified sex-specific pro-atherogenic responses to CS in the lipid profile, plaque area and composition and inflammatory markers. Males present a stronger impairment in endothelia dysfunction in WT mice, while females a stronger plaque burden in ApoE-/- mice exposed to CS. Elevated HDL and estrogens in males may offer partial protection against the harmful effects of CS. In contrast, elevated LDL and a pro-inflammatory state may promote a stronger pro-atherogenic phenotype in females exposed to CS.

cell biology↗

bioRxiv2021

Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human hearts

Phosphorylation and acetylation of sarcomeric proteins are important for fine-tuning myocardial contractility. Here, we used bottom-up proteomics and label-free quantification to identify novel post-translational modifications (PTMs) on beta-myosin heavy chain ({beta}-MHC) in normal and failing human heart tissues. We report six acetylated lysines and two phosphorylated residues: K34-Ac, K58-Ac, S210-P, K213-Ac, T215-P, K429-Ac, K951-Ac, and K1195-Ac. K951-Ac was significantly reduced in both ischemic and non-ischemic failing hearts compared to non-diseased hearts. Molecular dynamics simulations show that K951-Ac may impact stability of thick filament tail interactions and ultimately myosin head positioning. K58-Ac altered the solvent exposed SH3 domain surface - known for protein-protein interactions - but did not appreciably change motor domain conformation or dynamics under conditions studied. Together, K213-Ac/T215-P altered loop 1s structure and dynamics - known to regulate ADP-release, ATPase activity, and sliding velocity. Our study suggests that {beta}-MHC acetylation levels may be influenced more by the PTM location than the type of heart disease since less protected acetylation sites are reduced in both heart failure groups. Additionally, these PTMs have potential to modulate interactions between {beta}-MHC and other regulatory sarcomeric proteins, ADP-release rate of myosin, flexibility of the S2 region, and cardiac myofilament contractility in normal and heart failure hearts.

physiology↗