Person
Kojic, Snezana
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Biography and Research Interest
The Group for Muscle Cellular and Molecular Biology investigates different aspects of striated muscle structure and function. Our interest is in the molecular mechanisms of heart regeneration, skeletal muscle repair, and adaptation of muscle cells to stress. Our research focus is on the ANKRD1 and ANKRD2 genes and their roles in these processes.
ZEBARR concept
Heart diseases, and particularly myocardial infarction (MI), are the leading cause of death worldwide due to the inability of the injured human heart to regenerate. In contrast to humans, zebrafish regenerate injured heart, while both humans and zebrafish efficiently repair the wounded skeletal muscle. This implies that the key for unlocking the endogenous regenerative potential of the human heart may be hidden in regeneration-competent skeletal muscle. The ZEBARR project offers a novel approach to identify targets that might contribute to the restoration of impaired cardiac function by promoting myocardial regeneration. To expand our understanding of the cellular and molecular mechanisms involved in heart regeneration and skeletal muscle repair, we investigated the ankrd1a gene, which is activated during the healing of both the zebrafish heart and skeletal muscle, using the novel ZEBARR concept. We deciphered the function of zebrafish ankrd1a and identified its targets and associated pathways in cryoinjured heart and mechanically injured skeletal muscle, using loss-of-function zebrafish. We monitored outcomes of molecular and cellular processes contributing to heart regeneration and skeletal muscle repair by immunohistochemistry and fluorescent microscopy, analysis of gene expression and transcriptome profiling. Moreover, we investigated the possibility that ankrd1a mediates the beneficial effect of exercise on muscle regeneration and repair, thereby contributing to the healing process. We believe ANKRD1 is a potentially attractive target for translational studies to impact the field of regenerative biology and contribute to efforts directed toward the development of efficient therapies to promote the human heart's propensity for regeneration.
ankrd1a in skeletal muscle repair
Like mammals, zebrafish repair skeletal muscle through a multi-step process that involves satellite cell activation, differentiation of progenitor cells into myocytes, their fusion into myotubes, followed by myotube maturation and myofiber hypertrophy. Coordination and timely regulation of these events are essential for functional muscle recovery. We identify ankrd1a, a gene responsive to muscle stress, as a new player in the repair of adult zebrafish skeletal muscle and show its involvement in modulating molecular mechanisms behind myogenic cell differentiation. It is expressed in newly forming muscle fibers from the stage of myoblast-like cells to their differentiation into mature myofibers, as well as in the apparently intact muscle fibers that surround the injury. Loss of ankrd1a function alters regulatory pathways involved in muscle cell differentiation, contraction, and myocyte fusion, leading to the acceleration of myogenic differentiation. Our data point to ankrd1a as a novel marker of newly forming myofibers and a hallmark of the adaptive process occurring in the intact myofibers that are in contact with wounded tissue. Without affecting the main regulatory networks, ankrd1a fine-tunes skeletal muscle repair by preventing premature myogenic differentiation during injury repair, which itself could impair functional recovery.
ankrd1a in heart regeneration
In contrast to humans, zebrafish have an outstanding ability to regenerate injured heart through a highly orchestrated process involving all cardiac structures. To replace the lost myocardium, resident cardiomyocytes (CMs) dedifferentiate and proliferate, invading the injured area. The response of the myocardium is preceded by the activation of the epicardium and endocardium, which form active scaffolds to provide mechanical and paracrine support to guide regeneration. New CMs use protrusions to migrate and invade fibrotic injured tissue, replacing it with functional myocardium. We investigated the expression profile of the stress-responsive ankrd1a gene in different cardiac structures, at key time points during regeneration, and gain insight into its precise roles during zebrafish heart regeneration. In the TgBAC(ankrd1a:EGFP) reporter line, transgene upregulation was restricted to the myocardium, initiated as early as 15 hours post-cryoinjury, and consistently marked CMs bordering the injury or scar area during regeneration. Transcriptome profiling and immunostaining revealed a potential role of ankrd1a in regulating CMs' dedifferentiation, as well as changes in expression of genes associated with antigen presentation and extracellular matrix composition in the ankrd1a mutant. Our results indicate that the ankrd1a is dispensable for ventricle regeneration after cryoinjury and may be considered as a marker and fine-tuner in the healing process of injured cardiac muscle.
Our work in the field of zebrafish research was supported by the SCIENCE FUND of the Republic of Serbia, project title: Zebrafish ankrd1a as a common player in heart regeneration and skeletal muscle repair - a new prospect for unlocking regenerative potential of human heart – ZEBARR (7739807, 2022-2025.)
ZEBARR concept
Heart diseases, and particularly myocardial infarction (MI), are the leading cause of death worldwide due to the inability of the injured human heart to regenerate. In contrast to humans, zebrafish regenerate injured heart, while both humans and zebrafish efficiently repair the wounded skeletal muscle. This implies that the key for unlocking the endogenous regenerative potential of the human heart may be hidden in regeneration-competent skeletal muscle. The ZEBARR project offers a novel approach to identify targets that might contribute to the restoration of impaired cardiac function by promoting myocardial regeneration. To expand our understanding of the cellular and molecular mechanisms involved in heart regeneration and skeletal muscle repair, we investigated the ankrd1a gene, which is activated during the healing of both the zebrafish heart and skeletal muscle, using the novel ZEBARR concept. We deciphered the function of zebrafish ankrd1a and identified its targets and associated pathways in cryoinjured heart and mechanically injured skeletal muscle, using loss-of-function zebrafish. We monitored outcomes of molecular and cellular processes contributing to heart regeneration and skeletal muscle repair by immunohistochemistry and fluorescent microscopy, analysis of gene expression and transcriptome profiling. Moreover, we investigated the possibility that ankrd1a mediates the beneficial effect of exercise on muscle regeneration and repair, thereby contributing to the healing process. We believe ANKRD1 is a potentially attractive target for translational studies to impact the field of regenerative biology and contribute to efforts directed toward the development of efficient therapies to promote the human heart's propensity for regeneration.
ankrd1a in skeletal muscle repair
Like mammals, zebrafish repair skeletal muscle through a multi-step process that involves satellite cell activation, differentiation of progenitor cells into myocytes, their fusion into myotubes, followed by myotube maturation and myofiber hypertrophy. Coordination and timely regulation of these events are essential for functional muscle recovery. We identify ankrd1a, a gene responsive to muscle stress, as a new player in the repair of adult zebrafish skeletal muscle and show its involvement in modulating molecular mechanisms behind myogenic cell differentiation. It is expressed in newly forming muscle fibers from the stage of myoblast-like cells to their differentiation into mature myofibers, as well as in the apparently intact muscle fibers that surround the injury. Loss of ankrd1a function alters regulatory pathways involved in muscle cell differentiation, contraction, and myocyte fusion, leading to the acceleration of myogenic differentiation. Our data point to ankrd1a as a novel marker of newly forming myofibers and a hallmark of the adaptive process occurring in the intact myofibers that are in contact with wounded tissue. Without affecting the main regulatory networks, ankrd1a fine-tunes skeletal muscle repair by preventing premature myogenic differentiation during injury repair, which itself could impair functional recovery.
ankrd1a in heart regeneration
In contrast to humans, zebrafish have an outstanding ability to regenerate injured heart through a highly orchestrated process involving all cardiac structures. To replace the lost myocardium, resident cardiomyocytes (CMs) dedifferentiate and proliferate, invading the injured area. The response of the myocardium is preceded by the activation of the epicardium and endocardium, which form active scaffolds to provide mechanical and paracrine support to guide regeneration. New CMs use protrusions to migrate and invade fibrotic injured tissue, replacing it with functional myocardium. We investigated the expression profile of the stress-responsive ankrd1a gene in different cardiac structures, at key time points during regeneration, and gain insight into its precise roles during zebrafish heart regeneration. In the TgBAC(ankrd1a:EGFP) reporter line, transgene upregulation was restricted to the myocardium, initiated as early as 15 hours post-cryoinjury, and consistently marked CMs bordering the injury or scar area during regeneration. Transcriptome profiling and immunostaining revealed a potential role of ankrd1a in regulating CMs' dedifferentiation, as well as changes in expression of genes associated with antigen presentation and extracellular matrix composition in the ankrd1a mutant. Our results indicate that the ankrd1a is dispensable for ventricle regeneration after cryoinjury and may be considered as a marker and fine-tuner in the healing process of injured cardiac muscle.
Our work in the field of zebrafish research was supported by the SCIENCE FUND of the Republic of Serbia, project title: Zebrafish ankrd1a as a common player in heart regeneration and skeletal muscle repair - a new prospect for unlocking regenerative potential of human heart – ZEBARR (7739807, 2022-2025.)
Non-Zebrafish Publications