Biology subjects

Sriramula, S.

Publications and source records attributed to Sriramula, S..

3 recordsLinked to original sources

bioRxiv2026

High Intensity Interval Training in Aged Female Mice Preserves Physical, Cognitive, and Cardiovascular Function

BACKGROUNDAlong with advancing age comes declines in physical, cognitive, and cardiovascular function. This diminished capacity may lead to decreased ability to perform activities of daily living, disability onset, and loss of independence. Exercise is a regenerative medicine therapy that can mitigate this loss of function. High intensity interval training (HIIT) is an aerobic exercise paradigm consisting of intense activity periods interspersed with bouts of active recovery. Previously we demonstrated that HIIT preserved physical function in adult, middle-aged, and older male mice. However, whether HIIT preserves physical, cognitive, and cardiovascular function, mitigates frailty, and improves brain and heart health in older adult female mice remains unknown. HYPOTHESISCognitive, physical, and cardiovascular function in older adult female C57BL/6 will be preserved in exercised mice (HIIT) versus sedentary control (SED). METHODSMice (HIIT and SED, both n=9, 24m at end) were tested pre/post-intervention for physical (rotarod, treadmill, grip meter, inverted cling, voluntary wheel running, activity monitor), cognitive (open field, novel object recognition, puzzle box, y-maze), and cardiovascular (blood pressure, echocardiogram) function, body composition, and whole body calorimetry. The mice underwent 14-weeks of HIIT training with progressive volume and intensity. RESULTSHIIT significantly (p<0.05) increased or preserved function in many tests including: aerobic capacity (+71% HIIT versus, vs, no change, NC, in SED), four limb strength/endurance (-67% SED vs -28% HIIT), forelimb strength (-16% SED vs NC HIIT), overall motor function (NC SED vs +39% HIIT), executive function (NC SED vs +73% HIIT), and exploratory behavior, which improved across multiple tests with HIIT while remaining unchanged in SED. HIIT also reduced both systolic blood pressure by 12% (-17 mmHg) and mean arterial pressure by -16 mmHg. In addition, HIIT significantly reduced cardiac fibrosis, increased muscle fiber type 2a percentage, reduced IL-1{beta} expression in the hypothalamus, and mitigated frailty onset. CONCLUSIONHIIT significantly reduced age-related functional loss in all three domains assessed while preventing frailty onset in older adult females and improving markers of brain and heart health.

physiology↗

bioRxiv2025

Advanced Cardiac Organoid Model for Studying Doxorubicin-Induced Cardiotoxicity

Cardiac organoids provide an in vitro platform for studying heart disease mechanisms and drug responses. However, a major limitation is the immaturity of cardiomyocytes, restricting their ability to mimic adult cardiac physiology. Additionally, the inadequacy of commonly used extracellular matrices (ECM), which fail to replicate the biochemical and mechanical properties of natural heart tissue, poses significant challenges. Consequently, structural integrity in cardiac organoids is impaired. Moreover, scalability remains an obstacle, as conventional ECM substitutes hinder mass production of organoids for high-throughput toxicology screening. To overcome these challenges, we developed an advanced model promoting fibroblast-driven ECM self-secretion, enabling physiologically relevant tissue architecture and function. Using the ECM-free, mature cardiomyocyte-integrated organoid model, we investigated the cardiotoxicity of doxorubicin, a widely used chemotherapeutic agent known to impair cardiac function. Cardiomyocytes derived from induced pluripotent stem cells were characterized for maturity by immunostaining for cTNT and MYL2 alongside gene expression analysis. Organoids treated with doxorubicin showed reduced size and increased collagen deposition. These structural changes correlated with functional impairments, including decreased contraction rate and disrupted synchronous beating. In 2D culture, exposure to doxorubicin induced fibroblast activation, promoted endothelial-to-mesenchymal transition in endothelial cells, and triggered cytotoxic effects in cardiomyocytes. This study highlights the importance of ECM remodeling in advancing cardiac organoid models and demonstrates its potential for more accurate cardiotoxicity assessment. Addressing these limitations enhances the physiological relevance of cardiac organoid systems for drug safety assessment and cardiac disease modeling.

pharmacology and toxicology↗

bioRxiv2022

COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism

BackgroundViral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection. ObjectivesTo determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. MethodshACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone. ResultshACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p{square}<{square}0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone. ConclusionsOur observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination. FundingThis work was supported by grant from the State of North Carolina (PS, JE, DOR, RJS) and R21 NS122280 (RJS).

neuroscience↗