Biology subjects

Rostami, R.

Publications and source records attributed to Rostami, R..

3 recordsLinked to original sources

bioRxiv2023

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes

Age-related atrophy of skeletal muscle, is characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern how exercise serves to promote healthy muscle aging are unclear. Mitochondrial aging is associated with decreased mitochondrial capacity, so we sought to investigate how aging affects mitochondrial structure and potential age-related regulators. Specifically, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging requires further elucidation. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. Across 5 human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria we less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/566502v3_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1d2be0eorg.highwire.dtl.DTLVardef@bba6caorg.highwire.dtl.DTLVardef@1c335e5org.highwire.dtl.DTLVardef@10789c9_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Age-related skeletal muscle atrophy shows morphological alterations in mitochondrial structure associated with declining function. Our findings propose that exercise intervention may counteract these structural declines by reinstating levels of mitofusin 2, thus highlighting a potential mechanism by which exercise attenuates age-induced mitochondrial dysfunction. C_FIG

biophysics↗

bioRxiv2022

OPA1 Downregulation in Skeletal Muscle Induces MERC formation in an ATF4-Dependent Manner

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

biophysics↗

bioRxiv2019

Using the Concepts of Time-delayed Feedback Control in Biofeedback Systems in Children with ADD: A Preliminary Study

The reported efficacy of biofeedback is not consistent across studies. One issue that has not been addressed in previous studies is the effect of the reference signal in a biofeedback system.\n\nWe compared the effects of two different reference signals using a computational model and human experiments. One reference signal was fixed, and the other was variable and was designed based on time-delayed feedback control concepts. The computational model consists of a plant and a controller. Groups of typically developing and children with attention deficit disorder (ADD) participated in our experiments.\n\nThe computational model showed that time-delayed reference feedback control could have more positive effects on the performance than using a fixed reference signal. The model prediction was consistent with the results obtained from the experiments performed on children with ADD. However, in typically developing children, using time-delayed reference feedback control had a negative effect. Our preliminary results, which need to be investigated on more subjects, indicate the importance of selecting the reference signal in biofeedback systems according to the characteristics of each participant. The results remind the importance of \"single-case methodology\" in neurocognitive rehabilitation systems. Using computational concepts, some other predictions have also been provided, which need more investigations.

neuroscience↗