Ciliary Hedgehog signaling patterns the digestive system to generate mechanical forces driving elongation

How tubular organs elongate is poorly understood. We found that attenuated ciliary Hedgehog signaling in the gut wall impaired patterning of the circumferential smooth muscle and inhibited proliferation and elongation of developing intestine and esophagus. Similarly, ablation of gut-wall smooth muscle cells reduced lengthening. Disruption of ciliary Hedgehog signaling or removal of smooth muscle reduced residual stress within the gut wall and decreased activity of the mechanotransductive effector YAP. Removing YAP in the mesenchyme also reduced proliferation and elongation, but without affecting smooth muscle formation, suggesting that YAP interprets the smooth muscle-generated force to promote longitudinal growth. Additionally, we developed an intestinal culture system that recapitulates the requirements for cilia and mechanical forces in elongation. Pharmacologically activating YAP in this system restored elongation of cilia-deficient intestines. Thus, our results reveal that ciliary Hedgehog signaling patterns the circumferential smooth muscle to generate radial mechanical forces that activate YAP and elongate the gut.

COP Cells and Tissue Loss Syndromes: Frailty, Sarcopenia, and Osteoporosis

COP cells have been identified as having a potential role in the pathogenesis of tissue loss syndromes such as osteoporosis and frailty. This is based on the hypothesis that their dysregulation may cause a decrease in bone and muscle formation, which also increase the risk of adverse outcomes such as frailty and disability. Whereas high numbers of COP cells have been associated with osteoporosis and fracture healing, a low percentage of COP (%COP) cells have been associated with frailty and disability. In addition, low expression of lamin A (a protein of the inner nuclear envelope) in COP cells has also been associated with frailty and disability in older persons. In this session, the evidence on quantification methods for COP cells in clinical settings and the potential clinical use of COP cells in tissue loss syndromes will be discussed. This discussion will include current evidence supporting the use of COP cells as a biomarker or as a novel therapeutic approach to these age-related conditions.

Filopodia powered by class X myosin promote fusion of mammalian myoblasts

Skeletal muscle fibers are multinucleated cellular giants formed by the fusion of mononuclear myoblasts. Several molecules involved in myoblast fusion have been discovered, and finger-like projections coincident with myoblast fusion have also been implicated in the fusion process. The role of these cellular projections in muscle cell fusion was investigated herein. We demonstrate that these projections are filopodia generated by class X myosin (Myo10), an unconventional myosin motor protein specialized for filopodia. We further show that Myo10 is highly expressed by differentiating myoblasts, and Myo10 ablation inhibits both filopodia formation and myoblast fusion in vitro. In vivo, Myo10 labels regenerating muscle fibers associated with Duchenne muscular dystrophy and acute muscle injury. In mice, conditional loss of Myo10 from muscle-resident stem cells, known as satellite cells, severely impairs postnatal muscle regeneration. Furthermore, the muscle fusion proteins Myomaker and Myomixer are detected in myoblast filopodia. These data demonstrate that Myo10-driven filopodia facilitate multi-nucleated mammalian muscle formation.

HES and Mox genes are expressed during early mesoderm formation in a mollusk with putative ancestral features

The mesoderm is considered the youngest of the three germ layers. Although its morphogenesis has been studied in some metazoans, the molecular components underlying this process remain obscure for numerous phyla including the highly diverse Mollusca. Here, expression of Hairy and enhancer of split (HES), Mox, and myosin heavy chain (MHC) was investigated in Acanthochitona fascicularis, a representative of Polyplacophora with putative ancestral molluscan features. While AfaMHC is expressed throughout myogenesis, AfaMox1 is only expressed during early stages of mesodermal band formation and in the ventrolateral muscle, an autapomorphy of the polyplacophoran trochophore. Comparing our findings to previously published data across Metazoa reveals Mox expression in the mesoderm in numerous bilaterians including gastropods, polychaetes, and brachiopods. It is also involved in myogenesis in molluscs, annelids, tunicates, and craniates, suggesting a dual role of Mox in mesoderm and muscle formation in the last common bilaterian ancestor. AfaHESC2 is expressed in the ectoderm of the polyplacophoran gastrula and later in the mesodermal bands and in putative neural tissue, whereas AfaHESC7 is expressed in the trochoblasts of the gastrula and during foregut formation. This confirms the high developmental variability of HES gene expression and demonstrates that Mox and HES genes are pleiotropic.

PRC2: an epigenetic multiprotein complex with a key role in the development of rhabdomyosarcoma carcinogenesis

Skeletal muscle formation represents a complex of highly organized and specialized systems that are still not fully understood. Epigenetic systems underline embryonic development, maintenance of stemness, and progression of differentiation. Polycomb group proteins play the role of gene silencing of stemness markers that regulate muscle differentiation. Enhancer of Zeste EZH2 is the catalytic subunit of the complex that is able to trimethylate lysine 27 of histone H3 and induce silencing of the involved genes. In embryonal Rhabdomyosarcoma and several other tumors, EZH2 is often deregulated and, in some cases, is associated with tumor malignancy. This review explores the molecular processes underlying the failure of muscle differentiation with a focus on the PRC2 complex. These considerations could open new studies aimed at the development of new cutting-edge therapeutic strategies in the onset of Rhabdomyosarcoma.

Filopodia powered by class X myosin promote fusion of mammalian myoblasts

Skeletal muscle fibers are multinucleated cellular giants formed by the fusion of mononuclear myoblasts. Several molecules involved in myoblast fusion have been discovered, and finger-like projections coincident with myoblast fusion have also been implicated in the fusion process. The role of these cellular projections in muscle cell fusion was investigated herein. We demonstrate that these projections are filopodia generated by class X myosin (Myo10), an unconventional myosin motor protein specialized for filopodia. We further show that Myo10 is highly expressed by differentiating myoblasts, and Myo10 ablation inhibits both filopodia formation and myoblast fusion in vitro. In vivo, Myo10 labels regenerating muscle fibers associated with Duchenne muscular dystrophy and acute muscle injury. Conditional loss of Myo10 from muscle-resident stem cells, known as satellite cells, severely impairs postnatal muscle regeneration. Furthermore, the muscle fusion proteins Myomaker and Myomixer are detected in myoblast filopodia. These data demonstrate that Myo10-driven filopodia facilitate multi-nucleated mammalian muscle formation.

Zebrafish Danio rerio trunk muscle structure and growth from a spatial transcriptomics perspective

Compared to mammals, some fish exhibit indeterminate growth characteristics, meaning they can continue growing throughout their lives. Zebrafish trunk skeletal muscle can in general be classified into slow, intermediate, and fast based on morphological and physiological characteristics. After hatching, hyperplasia can be observed in the muscles of juvenile zebrafish, and with growth, hyperplasia in the fast muscles gradually decreases until it stagnates, after which fast muscle development relies on hypertrophy. In slow muscle, hyperplasia continues throughout life. Teleost muscle structure and growth has been described mainly by morphological and physiological features based on the expression of a limited number of proteins, transcripts, and metabolites. The details of mechanism remain unclear. Visium Spatial Gene Expression solution was used in this study. On the adult slide, 10 clusters were obtained based on whole gene expression similarities. The spatial expression of myosin heave chains, myosin light chains and myosin-binding proteins was investigated. GO enrichment analysis was also performed on different muscle regions of aged zebrafish. Dorsal and ventral slow muscles share the same processes such as myofibril assembly and muscle tissue development. On the larvae slide, 3 clusters were obtained, GO enrichment analysis suggest active muscle formation in zebrafish larvae.

An Analysis of Differentially Expressed Coding and Long Non-Coding RNAs in Multiple Models of Skeletal Muscle Atrophy

The loss of skeletal muscle mass (muscle atrophy or wasting) caused by aging, diseases, and injury decreases quality of life, survival rates, and healthy life expectancy in humans. Although long non-coding RNAs (lncRNAs) have been implicated in skeletal muscle formation and differentiation, their precise roles in muscle atrophy remain unclear. In this study, we used RNA-sequencing (RNA-Seq) to examine changes in the expression of lncRNAs in four muscle atrophy conditions (denervation, casting, fasting, and cancer cachexia) in mice. We successfully identified 33 annotated lncRNAs and 18 novel lncRNAs with common expression changes in all four muscle atrophy conditions. Furthermore, an analysis of lncRNA–mRNA correlations revealed that several lncRNAs affected small molecule biosynthetic processes during muscle atrophy. These results provide novel insights into the lncRNA-mediated regulatory mechanism underlying muscle atrophy and may be useful for the identification of promising therapeutic targets.

A Single-Center Trial to Evaluate the Efficacy and Tolerability of Four Microneedling Treatments on Fine Lines and Wrinkles of Facial and Neck Skin in Subjects With Fitzpatrick Skin Types I-IV: An Objective Assessment Using Non-Invasive Devices and 0.33mm Microbiopsies

Background While ablative techniques have been standard of care for the treatment of fine lines and wrinkles, microneedling is a minimally invasive alternative. Objectives The purpose of this study was to assess the efficacy of microneedling on facial and neck fine lines and wrinkles. Methods 35 subjects between 44 and 65 years old with Fitzpatrick skin types I-IV received four monthly microneedling treatments over the face and neck. Subjects returned one and three months post-treatment. At every visit, high-resolution ultrasonography, optical coherence tomography, transepidermal water loss and BTC-2000 were performed. 0.33mm microbiopsies were collected pre-treatment, before the fourth treatment and three months post-treatment. Results 32 subjects (93.75% female, 6.25% male) completed all seven visits. Facial dermal and epidermal density increased 101.86% and 19.28%, respectively from baseline at three months post-treatment. Facial elasticity increased 28.2% from baseline three months post-treatment. Facial attenuation coefficient increased 15.65% and 17.33% one and three months post-treatment. At study completion, blood flow 300µm deep decreased 25.8% in the face and 42.3% in the neck. Relative collagen type III and elastin gene expression was statistically higher three months post-treatment. However, total elastin protein levels unchanged compared to baseline. 58% of biopsies extracted three months post-treatment showed dermal muscle formation, compared to baseline 15.3%. Conclusions The results illustrate the effects of microneedling treatments. Non-invasive measurements and biopsy data showed changes in skin architecture and collagen/elastin gene expression suggesting skin rejuvenation, with new extracellular matrix production and muscle formation.