Irisin: An unveiled bridge between physical exercise and a healthy brain.

AIMS: Physical exercise has been widely recognized for its positive effects on health and well-being. Recently, the impact of exercise on the nervous system has gained attention, with evidence indicating improvements in attention, memory, neurogenesis, and the release of "happiness hormones." One potential mediator of these benefits is Irisin, a myokine induced by exercise that can cross the blood-brain barrier, reduce neuroinflammation, and counteract neurodegeneration. The objective of this study is to conduct a systematic review of animal trials to summarize the neuroprotective effects of Irisin injection in mitigating neuroinflammation and neurodegeneration. MATERIALS AND METHODS: Two independent reviewers screened three databases (PubMed, Embase, and Google Scholar) in November 2022. Animal studies assessing the neuroprotective effects of Irisin in mitigating neuroinflammation or counteracting neurodegeneration were included. The methodological quality of the included studies was assessed using SYRCLE's Risk of Bias tool. KEY FINDINGS: Twelve studies met the inclusion criteria. Irisin injection in rodents significantly reduced neuroinflammation, cytokine cascades, and neurodegeneration. It also protected neurons from damage and apoptosis, reduced oxidative stress, blood-brain barrier disruption, and neurobehavioral deficits following disease or injury. Various mechanisms were suggested to be responsible for these neuroprotective effects. Most of the included studies presented a low risk of bias based on SYRCLE's Risk of Bias tool. Irisin injection demonstrated the potential to alleviate neuroinflammation and counteract neurodegeneration in rodent models through multiple pathways. However, further research is needed to fully understand its mechanism of action and its potential applications in clinical practice and drug discovery.

Deconstructing the long-standing a priori assumption that serial homology generally involves ancestral similarity followed by anatomical divergence.

It has long been assumed that serial homologues are ancestrally similar-polysomerism resulting from a "duplication" or "repetition" of forms-and then often diverge-anisomerism, for example, as they become adapted to perform different tasks as is the case with the forelimb and hind limbs of humans. However, such an assumption, with crucial implications for comparative, evolutionary, and developmental biology, and for evolutionary developmental biology, has in general not really been tested by a broad analysis of the available empirical data. Perhaps not surprisingly, more recent anatomical comparisons, as well as molecular knowledge of how, for example, serial appendicular structures are patterned along with different anteroposterior regions of the body axis of bilateral animals, and how "homologous" patterning domains do not necessarily mark "homologous" morphological domains, are putting in question this paradigm. In fact, apart from showing that many so-called "serial homologues" might not be similar at all, recent works have shown that in at least some cases some "serial" structures are indeed more similar to each other in derived taxa than in phylogenetically more ancestral ones, as pointed out by authors such as Owen. In this article, we are taking a step back to question whether such assumptions are actually correct at all, in the first place. In particular, we review other cases of so-called "serial homologues" such as insect wings, arthropod walking appendages, Dipteran thoracic bristles, and the vertebrae, ribs, teeth, myomeres, feathers, and hairs of chordate animals. We show that: (a) there are almost never cases of true ancestral similarity; (b) in evolution, such structures-for example, vertebra-and/or their subparts-for example, "transverse processes"-many times display trends toward less similarity while in many others display trends toward more similarity, that is, one cannot say that there is a clear, overall trend to anisomerism.

Comparative anatomy of the fin muscles of non-sarcopterygian fishes, with notes on homology and evolution.

Limited gross anatomical information about the muscles of fins, in particular those of the median fins, creates substantial gaps in the comparative anatomy, homologies, and evolution of these muscles across fishes. The scarcity of data also makes it difficult to interpret results obtained in developmental studies done in model organisms, such as zebrafish. To overcome these gaps, we provide descriptions of the configuration of all appendicular muscles of Amia, median fins of Polypterus, and the dorsal and anal fins of Lepisosteus and Chondrostei. The musculature of other species, including sharks and sturgeons, is also revised. We describe muscles that were previously overlooked, report sexual dimorphism in the muscles of the anal fin of Polypterus, and reveal muscle variations within Polypterus males. Species dissected for the present study thus represent all major non-sarcopterygian extant clades of gnathostomes, i.e. Chondrichthyes, Polypteriformes, Chondrostei, Lepisosteiformes, Amiiformes and Teleostei. Moreover, we compare our observations with the relatively few works that have provided information about muscles of at least some fins of these taxa in order to provide a broad discussion on - and detailed schemes showing - the major evolutionary patterns within the appendicular musculature of these fishes. Such discussion provides an opportunity for a more comprehensive understanding of appendicular evolution and fish evolution in particular and of gnathostome and morphological evolution in general.

Development of human limb muscles based on whole-mount immunostaining and the links between ontogeny and evolution.

We provide the first detailed ontogenetic analysis of human limb muscles using whole-mount immunostaining. We compare our observations with the few earlier studies that have focused on the development of these muscles, and with data available on limb evolution, variations and pathologies. Our study confirms the transient presence of several atavistic muscles - present in our ancestors but normally absent from the adult human - during normal embryonic human development, and reveals the existence of others not previously described in human embryos. These atavistic muscles are found both as rare variations in the adult population and as anomalies in human congenital malformations, reinforcing the idea that such variations/anomalies can be related to delayed or arrested development. We further show that there is a striking difference in the developmental order of muscle appearance in the upper versus lower limbs, reinforcing the idea that the similarity between various distal upper versus lower limb muscles of tetrapod adults may be derived.

Effects of hyperthyroidism in the development of the appendicular skeleton and muscles of zebrafish, with notes on evolutionary developmental pathology (Evo-Devo-Path).

The hypothalamus-pituitary-thyroid (HPT) axis plays a crucial role in the metabolism, homeostasis, somatic growth and development of teleostean fishes. Thyroid hormones regulate essential biological functions such as growth and development, regulation of stress, energy expenditure, tissue compound, and psychological processes. Teleost thyroid follicles produce the same thyroid hormones as in other vertebrates: thyroxin (T4) and triiodothyronine (T3), making the zebrafish a very useful model to study hypo- and hyperthyroidism in other vertebrate taxa, including humans. Here we investigate morphological changes in T3 hyperthyroid cases in the zebrafish to better understand malformations provoked by alterations of T3 levels. In particular, we describe musculoskeletal abnormalities during the development of the zebrafish appendicular skeleton and muscles, compare our observations with those recently done by us on the normal developmental of the zebrafish, and discuss these comparisons within the context of evolutionary developmental pathology (Evo-Devo-Path), including human pathologies.

Musculoskeletal study of cebocephalic and cyclopic lamb heads illuminates links between normal and abnormal development, evolution and human pathologies.

This paper is part of the emerging field of Evolutionary Developmental Pathology, dedicated to study the links between normal and abnormal development, evolution and human pathologies. We analyzed the head musculoskeletal system of several 'natural mutant' newborn lambs displaying various degrees of abnormality, from mild defects to cebocephaly and to cyclopia, and compared them with humans. Interestingly, muscle defects are less marked than osteological ones, and contrarily to the latter they tend to display left-right assymetries. In individuals with cebocephalic and even cyclopic skulls almost all head muscles are normal. The very few exceptions are some extraocular muscles and facial muscles that normally attach to osteological structures that are missing in the abnormal heads: such muscles are instead attached to the 'nearest topological neighbor' of the missing osteological structure, a pattern also found in cyclopic humans. These observations support Alberch's ill-named "logic of monsters" - as a byproduct of strong developmental/topological constraints anatomical patterns tend to repeat themselves, even severe malformations displayed by distantly related taxa. They also support the idea that mammalian facial muscles reverted to an ancestral 'nearest-neighbor' muscle-bone type of attachment seen in non-vertebrate animals and in vertebrate limbs, but not in other vertebrate head muscles.

Development of zebrafish paired and median fin musculature: basis for comparative, developmental, and macroevolutionary studies.

The model organism Dario rerio (zebrafish) is widely used in evo-devo and comparative studies. Nevertheless, little is known about the development and differentiation of the appendicular musculature in this fish. In this study, we examined the development of the muscles of all five zebrafish fin types (pectoral, pelvic, anal, dorsal and caudal). We describe the development of the muscles of these fins, including some muscles that were never mentioned in the literature, such as the interhypurales of the caudal fin. Interestingly, these caudal muscles are present in early stages but absent in adult zebrafishes. We also compare various stages of zebrafish fin muscle development with the configuration found in other extant fishes, including non-teleostean actinopterygians as well as cartilaginous fishes. The present work thus provides a basis for future developmental, comparative, evolutionary and evo-devo studies and emphasizes the importance of developmental works on muscles for a more comprehensive understanding of the origin, development and evolution of the appendicular appendages of vertebrate animals.

Comparative anatomy of zebrafish paired and median fin muscles: basis for functional, developmental, and macroevolutionary studies.

In the last decades, Danio rerio became one of the most used model organisms in various evo-devo studies devoted to the fin skeletal anatomy and fin-limb transition. Surprisingly, there is not even a single paper about the detailed anatomy of the adult muscles of the five fin types of this species. To facilitate more integrative developmental, functional, genetic, and evolutionary studies of the appendicular musculoskeletal system of the zebrafish and to provide a basis for further comparisons with other fishes and tetrapods, we describe here the identity, overall configuration, and attachments of appendicular muscles in a way that can be easily understood and implemented by non-anatomist researchers. We show that the muscle pattern of the caudal fin is very different from patterns seen in other fins but is very consistent within teleosts. Our observations support the idea of the developmental and evolutionary distinction of the caudal fin and point out that the musculature of the adult zebrafish pectoral and pelvic fins is in general very similar. Both paired fins have superficial and deep layers of abductors and adductors going to all/most rays plus the dorsal and ventral arrectors going only to the first ray. Nevertheless, we noted three major differences between the pelvic and pectoral fins of adult zebrafishes: (i) the pectoral girdle lacks a retractor muscle, which is present in the pelvic girdle - the retractor ischii; (ii) the protractor of the pelvic girdle is an appendicular/trunk muscle, while that of the pectoral girdle is a branchiomeric muscle; (iii) the first ray of the pectoral fin is moved by an additional arrector-3. The anal and dorsal fins consist of serially repeated units, each of which comprises one half-ray and three appendicular muscles (one erector, depressor, and inclinator) on each side of the body. The outermost rays are attachment points for the longitudinal protractor and retractor. Based on our results, we discuss whether the pectoral appendage might evolutionarily be closer to the head than to the pelvic appendage and whether the pelvic appendage might have been derived from the trunk/median fins. We discuss a hypothesis of paired fin origin that is a hybrid of the fin-fold and Gegenbaur's theories. Lastly, our data indicate that D. rerio is indeed an appropriate model organism for the appendicular musculature of teleosts in particular and, at least in the case of the paired fins, also of actinopterygians as a whole.

CRISPR/Cas9 and active genetics-based trans-species replacement of the endogenous Drosophila kni-L2 CRM reveals unexpected complexity.

The knirps (kni) locus encodes transcription factors required for induction of the L2 wing vein in Drosophila. Here, we employ diverse CRISPR/Cas9 genome editing tools to generate a series of targeted lesions within the endogenous cis-regulatory module (CRM) required for kni expression in the L2 vein primordium. Phenotypic analysis of these 'in locus' mutations based on both expression of Kni protein and adult wing phenotypes, reveals novel unexpected features of L2-CRM function including evidence for a chromosome pairing-dependent process that promotes transcription. We also demonstrate that self-propagating active genetic elements (CopyCat elements) can efficiently delete and replace the L2-CRM with orthologous sequences from other divergent fly species. Wing vein phenotypes resulting from these trans-species enhancer replacements parallel features of the respective donor fly species. This highly sensitive phenotypic readout of enhancer function in a native genomic context reveals novel features of CRM function undetected by traditional reporter gene analysis.

Specific expression and function of the Six3 optix in Drosophila serially homologous organs.

Organ size and pattern results from the integration of two positional information systems. One global information system, encoded by the Hox genes, links organ type with position along the main body axis. Within specific organs, local information is conveyed by signaling molecules that regulate organ growth and pattern. The mesothoracic (T2) wing and the metathoracic (T3) haltere of Drosophila represent a paradigmatic example of this coordination. The Hox gene Ultrabithorax (Ubx), expressed in the developing T3, selects haltere identity by, among other processes, modulating the production and signaling efficiency of Dpp, a BMP2-like molecule that acts as a major regulator of size and pattern. However, the mechanisms of the Hox-signal integration in this well-studied system are incomplete. Here, we have investigated this issue by studying the expression and function of the Six3 transcription factor optix during Drosophila wing and haltere development. We find that in both organs, Dpp defines the expression domain of optix through repression, and that the specific position of this domain in wing and haltere seems to reflect the differential signaling profile among these organs. We show that optix expression in wing and haltere primordia is conserved beyond Drosophila in other higher diptera. In Drosophila, optix is necessary for the growth of wing and haltere. In the wing, optix is required for the growth of the most anterior/proximal region (the 'marginal cell') and for the correct formation of sensory structures along the proximal anterior wing margin; the halteres of optix mutants are also significantly reduced. In addition, in the haltere, optix is necessary for the suppression of sensory bristles.

Size relationships of different body parts in the three dipteran species Drosophila melanogaster, Ceratitis capitata and Musca domestica.

Body size is an integral feature of an organism that influences many aspects of life such as fecundity, life span and mating success. Size of individual organs and the entire body size represent quantitative traits with a large reaction norm, which are influenced by various environmental factors. In the model system Drosophila melanogaster, pupal size and adult traits, such as tibia and thorax length or wing size, accurately estimate the overall body size. However, it is unclear whether these traits can be used in other flies. Therefore, we studied changes in size of pupae and adult organs in response to different rearing temperatures and densities for D. melanogaster, Ceratitis capitata and Musca domestica. We confirm a clear sexual size dimorphism (SSD) for Drosophila and show that the SSD is less uniform in the other species. Moreover, the size response to changing growth conditions is sex dependent. Comparison of static and evolutionary allometries of the studied traits revealed that response to the same environmental variable is genotype specific but has similarities between species of the same order. We conclude that the value of adult traits as estimators of the absolute body size may differ among species and the use of a single trait may result in wrong assumptions. Therefore, we suggest using a body size coefficient computed from several individual measurements. Our data is of special importance for monitoring activities of natural populations of the three dipteran flies, since they are harmful species causing economical damage (Drosophila, Ceratitis) or transferring diseases (Musca).

Decoding of exon splicing patterns in the human RUNX1-RUNX1T1 fusion gene.

The t(8;21) translocation is the most widespread genetic defect found in human acute myeloid leukemia. This translocation results in the RUNX1-RUNX1T1 fusion gene that produces a wide variety of alternative transcripts and influences the course of the disease. The rules of combinatorics and splicing of exons in the RUNX1-RUNX1T1 transcripts are not known. To address this issue, we developed an exon graph model of the fusion gene organization and evaluated its local exon combinatorics by the exon combinatorial index (ECI). Here we show that the local exon combinatorics of the RUNX1-RUNX1T1 gene follows a power-law behavior and (i) the vast majority of exons has a low ECI, (ii) only a small part is represented by "exons-hubs" of splicing with very high ECI values, and (iii) it is scale-free and very sensitive to targeted skipping of "exons-hubs". Stochasticity of the splicing machinery and preferred usage of exons in alternative splicing can explain such behavior of the system. Stochasticity may explain up to 12% of the ECI variance and results in a number of non-coding and unproductive transcripts that can be considered as a noise. Half-life of these transcripts is increased due to the deregulation of some key genes of the nonsense-mediated decay system in leukemia cells. On the other hand, preferred usage of exons may explain up to 75% of the ECI variability. Our analysis revealed a set of splicing-related cis-regulatory motifs that can explain "attractiveness" of exons in alternative splicing but only when they are considered together. Cis-regulatory motifs are guides for splicing trans-factors and we observed a leukemia-specific profile of expression of the splicing genes in t(8;21)-positive blasts. Altogether, our results show that alternative splicing of the RUNX1-RUNX1T1 transcripts follows strict rules and that the power-law component of the fusion gene organization confers a high flexibility to this process.