Biology subjects

Ananthamohan, K.

Publications and source records attributed to Ananthamohan, K..

3 recordsLinked to original sources

bioRxiv2024

Fast Myosin Binding Protein-C is a Vital Regulator in Young and Aged Fast Skeletal Muscle Homeostasis

BackgroundSkeletal muscle plays a vital role in voluntary motion and locomotion. Fast-twitch muscle fibers are characterized by their rapid contraction kinetics, high force generation capacity, and a distinct gene expression profile compared to slow-twitch fibers. Skeletal myosin binding protein-C (MyBP-C) paralogs, slow (sMyBP-C) and fast (fMyBP-C), interact with myosin and actin filaments within sarcomeres to modulate force development during contraction. These paralogs are differentially expressed in muscle fibers, with fMyBP-C predominantly expressed in the fast-twitch fibers. However, the role of fMyBP-C in skeletal muscle disease states and aging remains poorly understood. This study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology. MethodsAdult skeletal muscle samples aged 2[~]7 months from male and female wild-type, db/db, MDX, ECC injury model, were used to determine the differential expression of fMyBP-C. Next, Mybpc2 knockout (C2-/-) young (3[~]5 months) and old (22 months) male mice were used to define the role of fMyBP-C in aging. Western immunoblotting was employed to analyze the expression of fMyBP-C and sMyBP-C and the phosphorylation status of sMyBP-C. The impact of C2-/- and aging on the fiber type, size, and number as well as general muscle structure was assessed by immunohistochemistry and electron microscopy. The functional effect of C2-/- and aging was measured in terms of in vivo and ex vivo muscle force generation. Lastly, RNA sequencing was performed to identify the molecular pathways dysregulated in the C2-/- mediated muscle dysfunction in young and old mice. ResultsfMyBP-C was significantly reduced with a modest compensatory upregulation of sMyBP-C in the diseased fast-twitch muscles. fMyBP-C has a significantly higher expression in the male skeletal muscles compared to females. Further studies using young male C2-/- mice showed a significant reduction in isometric tetanic force generation and relaxation rate, fiber type switching, atrophy, and altered gene expressions related to muscle function and metabolism compared to wild-type mice. Similarly, compared to their wild-type counterparts, aged male C2-/- mice display significant deficits in muscle strength, endurance, and survival rate, accompanied by changes in muscle fiber size and molecular signaling pathways critical for muscle homeostasis. ConclusionfMyBP-C is an important regulator of muscle function and homeostasis in young and aged male fast-twitch muscle fibers. The absence of fMyBP-C aggravates the effect of aging on muscle structure and function. fMyBP-C has the potential to be a therapeutic target to modulate muscle wasting caused by aging and disease.

physiology↗

bioRxiv2024

A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension

BACKGROUNDPrimary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the co-morbid cardiovascular disease risk factors that confound studies in adults. METHODSYouths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTSVASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONSThe findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

genomics↗

bioRxiv2019

A common tag nucleotide variant in MMP7 promoter increases risk for hypertension via enhanced interactions with CREB transcription factor

MMP7 (Matrilysin), a potent extracellular matrix degrading enzyme with wide substrate specificity, is emerging as a new regulator of cardiovascular diseases including coronary artery disease and atherosclerosis. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we first probed for the association of a tag single nucleotide polymorphism (SNP) in the MMP7 gene promoter (-181A/G; rs11568818) with hypertension in an urban south Indian population (n=1517). The heterozygous A/G genotype showed a strong association with hypertension as compared to the A/A wild-type genotype (OR=1.641, 95% CI=1.276-2.109; p=1x10-4); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than AA genotype subjects. The study was replicated in a north Indian population (n=977) as well (OR=1.520, 95% CI =1.106-2.090; p=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele. Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the transcription factor CREB to the -181G promoter. In corroboration, over-expression/down-regulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. Further, the -181G promoter also displayed an enhanced response to hypoxia and epinephrine-treatment. The higher promoter activity of -181G allele also translated to increased MMP7 protein levels. Indeed, MMP7-181A/G heterozygous individuals displayed elevated plasma MMP7 levels which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter SNP increased expression of MMP7 under pathophysiological (such as hypoxic stress and catecholamine excess) conditions via increased interactions with the transcription factor CREB and enhanced the risk for hypertension in its carriers.

genetics↗