On the role of dysferlin in striated muscle: membrane repair, t-tubules and Ca2+ handling.

Dysferlin is a 237 kDa membrane-associated protein characterised by multiple C2 domains with a diverse role in skeletal and cardiac muscle physiology. Mutations in DYSF are known to cause various types of human muscular dystrophies, known collectively as dysferlinopathies, with some patients developing cardiomyopathy. A myriad of in vitro membrane repair studies suggest that dysferlin plays an integral role in the membrane repair complex in skeletal muscle. In comparison, less is known about dysferlin in the heart, but mounting evidence suggests that dysferlin's role is similar in both muscle types. Recent findings have shown that dysferlin regulates Ca2+ handling in striated muscle via multiple mechanisms and that this becomes more important in conditions of stress. Maintenance of the transverse (t)-tubule network and the tight coordination of excitation-contraction coupling are essential for muscle contractility. Dysferlin regulates the maintenance and repair of t-tubules, and it is suspected that dysferlin regulates t-tubules and sarcolemmal repair through a similar mechanism. This review focuses on the emerging complexity of dysferlin's activity in striated muscle. Such insights will progress our understanding of the proteins and pathways that regulate basic heart and skeletal muscle function and help guide research into striated muscle pathology, especially that which arises due to dysferlin dysfunction.

ATP-Induced Contractile Response of Esophageal Smooth Muscle in Mice.

The tunica muscularis of mammalian esophagi is composed of striated muscle and smooth muscle. Contraction of the esophageal striated muscle portion is mainly controlled by cholinergic neurons. On the other hand, smooth muscle contraction and relaxation are controlled not only by cholinergic components but also by non-cholinergic components in the esophagus. Adenosine triphosphate (ATP) is known to regulate smooth muscle contraction and relaxation in the gastrointestinal tract via purinergic receptors. However, the precise mechanism of purinergic regulation in the esophagus is still unclear. Therefore, the aim of the present study was to clarify the effects of ATP on the mechanical responses of the esophageal muscle in mice. An isolated segment of the mouse esophagus was placed in a Magnus's tube and longitudinal mechanical responses were recorded. Exogenous application of ATP induced contractile responses in the esophageal preparations. Tetrodotoxin, a blocker of voltage-dependent sodium channels in neurons and striated muscle, did not affect the ATP-induced contraction. The ATP-evoked contraction was blocked by pretreatment with suramin, a purinergic receptor antagonist. RT-PCR revealed the expression of mRNA of purinergic receptor genes in the mouse esophageal tissue. The findings suggest that purinergic signaling might regulate the motor activity of mouse esophageal smooth muscle.

Alary muscles and thoracic alary-related muscles are atypical striated muscles involved in maintaining the position of internal organs.

Alary muscles (AMs) have been described as a component of the cardiac system in various arthropods. Lineage-related thoracic muscles (TARMs), linking the exoskeleton to specific gut regions, have recently been discovered in Drosophila Asymmetrical attachments of AMs and TARMs, to the exoskeleton on one side and internal organs on the other, suggested an architectural function in moving larvae. Here, we analysed the shape and sarcomeric organisation of AMs and TARMs, and imaged their atypical deformability in crawling larvae. We then selectively eliminated AMs and TARMs by targeted apoptosis. Elimination of AMs revealed that AMs are required for suspending the heart in proper intra-haemocelic position and for opening of the heart lumen, and that AMs constrain the curvature of the respiratory tracheal system during crawling; TARMs are required for proper positioning of visceral organs and efficient food transit. AM/TARM cardiac versus visceral attachment depends on Hox control, with visceral attachment being the ground state. TARMs and AMs are the first example of multinucleate striated muscles connecting the skeleton to the cardiac and visceral systems in bilaterians, with multiple physiological functions.

One size does not fit all: diversity of length-force properties of obliquely striated muscles.

Obliquely striated muscles occur in 17+ phyla, likely evolving repeatedly, yet the implications of oblique striation for muscle function are unknown. Contrary to the belief that oblique striation allows high force output over extraordinary length ranges (i.e. superelongation), recent work suggests diversity in operating length ranges and length-force relationships. We hypothesize oblique striation evolved to increase length-force relationship flexibility. We predict that superelongation is not a general characteristic of obliquely striated muscles and instead that length-force relationships vary with operating length range. To test these predictions, we measured length-force relationships of five obliquely striated muscles from inshore longfin squid, Doryteuthis pealeii: tentacle, funnel retractor and head retractor longitudinal fibers, and arm and fin transverse fibers. Consistent with superelongation, the tentacle length-force relationship had a long descending limb, whereas all others exhibited limited descending limbs. The ascending limb at 0.6P0 was significantly broader (P<0.001) for the tentacle length-force relationship (0.43±0.04L0; where L0 is the preparation length that produced peak isometric stress, P0) than for the arm (0.29±0.03L0), head retractor (0.24±0.06L0), fin (0.20±0.04L0) and funnel retractor (0.27±0.03L0). The fin's narrow ascending limb differed significantly from those of the arm (P=0.004) and funnel retractor (P=0.012). We further characterized the tentacle preparation's maximum isometric stress (315±78 kPa), maximum unloaded shortening velocity (2.97±0.55L0 s-1) and ultrastructural traits (compared with the arm), which may explain its broader length-force relationship. Comparison of obliquely striated muscles across taxa revealed length-force relationship diversity, with only two species exhibiting superelongation.

The myosin interacting-heads motif present in live tarantula muscle explains tetanic and posttetanic phosphorylation mechanisms.

Striated muscle contraction involves sliding of actin thin filaments along myosin thick filaments, controlled by calcium through thin filament activation. In relaxed muscle, the two heads of myosin interact with each other on the filament surface to form the interacting-heads motif (IHM). A key question is how both heads are released from the surface to approach actin and produce force. We used time-resolved synchrotron X-ray diffraction to study tarantula muscle before and after tetani. The patterns showed that the IHM is present in live relaxed muscle. Tetanic contraction produced only a very small backbone elongation, implying that mechanosensing-proposed in vertebrate muscle-is not of primary importance in tarantula. Rather, thick filament activation results from increases in myosin phosphorylation that release a fraction of heads to produce force, with the remainder staying in the ordered IHM configuration. After the tetanus, the released heads slowly recover toward the resting, helically ordered state. During this time the released heads remain close to actin and can quickly rebind, enhancing the force produced by posttetanic twitches, structurally explaining posttetanic potentiation. Taken together, these results suggest that, in addition to stretch activation in insects, two other mechanisms for thick filament activation have evolved to disrupt the interactions that establish the relaxed helices of IHMs: one in invertebrates, by either regulatory light-chain phosphorylation (as in arthropods) or Ca2+-binding (in mollusks, lacking phosphorylation), and another in vertebrates, by mechanosensing.

PolySTest: Robust Statistical Testing of Proteomics Data with Missing Values Improves Detection of Biologically Relevant Features.

Statistical testing remains one of the main challenges for high-confidence detection of differentially regulated proteins or peptides in large-scale quantitative proteomics experiments by mass spectrometry. Statistical tests need to be sufficiently robust to deal with experiment intrinsic data structures and variations and often also reduced feature coverage across different biological samples due to ubiquitous missing values. A robust statistical test provides accurate confidence scores of large-scale proteomics results, regardless of instrument platform, experimental protocol and software tools. However, the multitude of different combinations of experimental strategies, mass spectrometry techniques and informatics methods complicate the decision of choosing appropriate statistical approaches. We address this challenge by introducing PolySTest, a user-friendly web service for statistical testing, data browsing and data visualization. We introduce a new method, Miss test, that simultaneously tests for missingness and feature abundance, thereby complementing common statistical tests by rescuing otherwise discarded data features. We demonstrate that PolySTest with integrated Miss test achieves higher confidence and higher sensitivity for artificial and experimental proteomics data sets with known ground truth. Application of PolySTest to mass spectrometry based large-scale proteomics data obtained from differentiating muscle cells resulted in the rescue of 10-20% additional proteins in the identified molecular networks relevant to muscle differentiation. We conclude that PolySTest is a valuable addition to existing tools and instrument enhancements that improve coverage and depth of large-scale proteomics experiments. A fully functional demo version of PolySTest and Miss test is available via http://computproteomics.bmb.sdu.dk/Apps/PolySTest.

Phospholipids: Identification and Implication in Muscle Pathophysiology.

Phospholipids (PLs) are amphiphilic molecules that were essential for life to become cellular. PLs have not only a key role in compartmentation as they are the main components of membrane, but they are also involved in cell signaling, cell metabolism, and even cell pathophysiology. Considered for a long time to simply be structural elements of membranes, phospholipids are increasingly being viewed as sensors of their environment and regulators of many metabolic processes. After presenting their main characteristics, we expose the increasing methods of PL detection and identification that help to understand their key role in life processes. Interest and importance of PL homeostasis is growing as pathogenic variants in genes involved in PL biosynthesis and/or remodeling are linked to human diseases. We here review diseases that involve deregulation of PL homeostasis and present a predominantly muscular phenotype.

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease.

The well-orchestrated turnover of proteins in cross-striated muscles is one of the fundamental processes required for muscle cell function and survival. Dysfunction of the intricate protein degradation machinery is often associated with development of cardiac and skeletal muscle myopathies. Most muscle proteins are degraded by the ubiquitin-proteasome system (UPS). The UPS involves a number of enzymes, including E3-ligases, which tightly control which protein substrates are marked for degradation by the proteasome. Recent data reveal that E3-ligases of the cullin family play more diverse and crucial roles in cross striated muscles than previously anticipated. This review highlights some of the findings on the multifaceted functions of cullin-RING E3-ligases, their substrate adapters, muscle protein substrates, and regulatory proteins, such as the Cop9 signalosome, for the development of cross striated muscles, and their roles in the etiology of myopathies.

Characterization and mechanism of the esophago-esophageal contractile reflex of the striated muscle esophagus.

An esophago-esophageal contractile reflex (EECR) of the cervical esophagus has been identified in humans. The aim of this study was to characterize and determine the mechanisms of the EECR. Cats (n = 35) were decerebrated, electrodes were placed on pharynx and cervical esophagus, and esophageal motility was recorded using manometry. All areas of esophagus were distended to locate and quantify the EECR. The effects of esophageal perfusion of NaCl or HCl, vagus nerve or pharyngoesophageal nerve (PEN) transection, or hexamethonium administration (5 mg/kg iv) were determined. We found that distension of the esophagus at all locations activated EECR rostral to stimulus only. EECR response was greatest when the esophagus 2.5-11.5 cm from cricopharyngeus (CP) was distended. HCl perfusion activated repetitively an EECR-like response of the proximal esophagus only within 2 min, and after ~20 min EECR was inhibited. Transection of PEN blocked or inhibited EECR 1-7 cm from CP, and vagotomy blocked EECR at all locations. Hexamethonium blocked EECR at 13 and 16 cm from CP but sensitized its activation at 1-7 cm from CP. EECR of the entire esophagus exists, which is directed in the orad direction only. EECR of striated muscle esophagus is mediated by vagus nerve and PEN and inhibited by mechanoreceptors of smooth muscle esophagus. EECR of smooth muscle esophagus is mediated by enteric nervous system and vagus nerve. Activation of EECR of the striated muscle esophagus is initially sensitized by HCl exposure, which may have a role in prevention of supraesophageal reflux.NEW & NOTEWORTHY An esophago-esophageal contractile reflex (EECR) exists, which is directed in the orad direction only. EECR of the proximal esophagus can appear similar to and be mistaken for secondary peristalsis. The EECR of the striated muscle is mediated by the vagus nerve and pharyngoesophageal nerve and inhibited by mechanoreceptor input from the smooth muscle esophagus. HCl perfusion initially sensitizes activation of the EECR of the striated muscle esophagus, which may participate in prevention of supraesophageal reflux.

Invertebrate troponin: Insights into the evolution and regulation of striated muscle contraction.

The troponin complex plays a central role in regulating the contraction and relaxation of striated muscles. Among the three protein subunits of troponin, the calcium receptor subunit, TnC, belongs to the calmodulin family of calcium signaling proteins whereas the inhibitory subunit, TnI, and tropomyosin-binding/thin filament-anchoring subunit, TnT, are striated muscle-specific regulatory proteins. TnI and TnT emerged early in bilateral symmetric invertebrate animals and have co-evolved during the 500-700 million years of muscle evolution. To understand the divergence as well as conservation of the structures of TnI and TnT in invertebrate and vertebrate organisms adds novel insights into the structure-function relationship of troponin and the muscle type isoforms of TnI and TnT. Based on the significant growth of genomic database of multiple species in the past decade, this focused review studied the primary structure features of invertebrate troponin subunits in comparisons with the vertebrate counterparts. The evolutionary data demonstrate valuable information for a better understanding of the thin filament regulation of striated muscle contractility in health and diseases.

Parasitic gut infection in Libellula pulchella causes functional and molecular resemblance of dragonfly flight muscle to skeletal muscle of obese vertebrates.

We previously demonstrated the existence of a naturally occurring metabolic disease phenotype in Libellula pulchella dragonflies that shows high similarity to vertebrate obesity and type II diabetes, and is caused by a protozoan gut parasite. To further mechanistic understanding of how this metabolic disease phenotype affects fitness of male L. pulchella in vivo, we examined infection effects on in situ muscle performance and molecular traits relevant to dragonfly flight performance in nature. Importantly, these traits were previously shown to be affected in obese vertebrates. Similarly to obesity effects in rat skeletal muscle, dragonfly gut infection caused a disruption of relationships between body mass, flight muscle power output and alternative pre-mRNA splicing of troponin T, which affects muscle calcium sensitivity and performance in insects and vertebrates. In addition, when simulated in situ to contract at cycle frequencies ranging from 20 to 45 Hz, flight muscles of infected individuals displayed a left shift in power-cycle frequency curves, indicating a significant reduction in their optimal cycle frequency. Interestingly, these power-cycle curves were similar to those produced by flight muscles of non-infected teneral (i.e. physiologically immature) adult L. pulchella males. Overall, our results indicate that the effects of metabolic disease on skeletal muscle physiology in natural insect systems are similar to those observed in vertebrates maintained in laboratory settings. More generally, they indicate that study of natural, host-parasite interactions can contribute important insight into how environmental factors other than diet and exercise may contribute to the development of metabolic disease phenotypes.

The effects of microenergy acoustic pulses on animal model of obesity-associated stress urinary incontinence. Part 2: In situ activation of pelvic floor and urethral striated muscle progenitor cells.

AIM: To investigate the possibility and mechanism of microenergy acoustic pulses (MAP) for activating tissue resident stem/progenitor cells within pelvic and urethral muscle and possible mechanism. METHODS: The female Zucker Lean and Zucker Fatty rats were randomly divided into four groups: ZL control, ZLMAP, ZF control, and ZFMAP. MAP was applied at 0.033 mJ/mm2 , 3 Hz for 500 pulses, and the urethra and pelvic floor muscles of each rat was then harvested for cell isolation and flow cytometry assay. Freshly isolated cells were analyzed by flow cytometry for Pax-7, Int-7α, H3P, and EdU expression. Meanwhile, pelvic floor muscle-derived stem cells (MDSCs) were harvested through magnetic-activated cell sorting, MAP was then applied to MDSCs to assess the mechanism of stem cell activation. RESULTS: Obesity reduced EdU-label-retaining cells and satellite cells in both pelvic floor muscle and urethra, while MAP activated those cells and enhanced cell proliferation, which promoted regeneration of striated muscle cells of the pelvic floor and urethral sphincter. Activation of focal adhesion kinase (FAK)/AMP-activated protein kinase (AMPK) /Wnt/ß-catenin signaling pathways by MAP is the potential mechanism. CONCLUSIONS: MAP treatment activated tissue resident stem cells within pelvic floor and urethral muscle in situ via activating FAK-AMPK and Wnt/ß-catenin signaling pathway.

Special Issue: The Actin-Myosin Interaction in Muscle: Background and Overview.

Muscular contraction is a fundamental phenomenon in all animals; without it life as we know it would be impossible. The basic mechanism in muscle, including heart muscle, involves the interaction of the protein filaments myosin and actin. Motility in all cells is also partly based on similar interactions of actin filaments with non-muscle myosins. Early studies of muscle contraction have informed later studies of these cellular actin-myosin systems. In muscles, projections on the myosin filaments, the so-called myosin heads or cross-bridges, interact with the nearby actin filaments and, in a mechanism powered by ATP-hydrolysis, they move the actin filaments past them in a kind of cyclic rowing action to produce the macroscopic muscular movements of which we are all aware. In this special issue the papers and reviews address different aspects of the actin-myosin interaction in muscle as studied by a plethora of complementary techniques. The present overview provides a brief and elementary introduction to muscle structure and function and the techniques used to study it. It goes on to give more detailed descriptions of what is known about muscle components and the cross-bridge cycle using structural biology techniques, particularly protein crystallography, electron microscopy and X-ray diffraction. It then has a quick look at muscle mechanics and it summarises what can be learnt about how muscle works based on the other studies covered in the different papers in the special issue. A picture emerges of the main molecular steps involved in the force-producing process; steps that are also likely to be seen in non-muscle myosin interactions with cellular actin filaments. Finally, the remarkable advances made in studying the effects of mutations in the contractile assembly in causing specific muscle diseases, particularly those in heart muscle, are outlined and discussed.

Estimation of Forces on Actin Filaments in Living Muscle from X-ray Diffraction Patterns and Mechanical Data.

Many biological processes are triggered or driven by mechanical forces in the cytoskeletal network, but these transducing forces have rarely been assessed. Striated muscle, with its well-organized structure provides an opportunity to assess intracellular forces using small-angle X-ray fiber diffraction. We present a new methodology using Monte Carlo simulations of muscle contraction in an explicit 3D sarcomere lattice to predict the fiber deformations and length changes along thin filaments during contraction. Comparison of predicted diffraction patterns to experimental meridional X-ray reflection profiles allows assessment of the stepwise changes in intermonomer spacings and forces in the myofilaments within living muscle cells. These changes along the filament length reflect the effect of forces from randomly attached crossbridges. This approach enables correlation of the molecular events, such as the current number of attached crossbridges and the distributions of crossbridge forces to macroscopic measurements of force and length changes during muscle contraction. In addition, assessments of fluctuations in local forces in the myofilaments may reveal how variations in the filament forces acting on signaling proteins in the sarcomere M-bands and Z-discs modulate gene expression, protein synthesis and degradation, and as well to mechanisms of adaptation of muscle in response to changes in mechanical loading.

Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology.

The Myosin Binding Protein-C (MyBP-C) family is a group of sarcomeric proteins important for striated muscle structure and function. Comprising approximately 2% of the myofilament mass, MyBP-C has important roles in both contraction and relaxation. Three paralogs of MyBP-C are encoded by separate genes with distinct expression profiles in striated muscle. In mammals, cardiac MyBP-C is limited to the heart, and it is the most extensively studied owing to its involvement in cardiomyopathies. However, the roles of two skeletal paralogs, slow and fast, in muscle biology remain poorly characterized. Nonetheless, both have been recently implicated in the development of skeletal myopathies. This calls for a better understanding of their function in the pathophysiology of distal arthrogryposis. This review characterizes MyBP-C as a whole and points out knowledge gaps that still remain with respect to skeletal MyBP-C.

Fin and body neuromuscular coordination changes during walking and swimming in Polypterus senegalus.

The ability to modulate the function of muscle is integral to an animal's ability to function effectively in the face of widely disparate challenges. This modulation of function can manifest through short-term changes in neuromuscular control, but also through long-term changes in force profiles, fatiguability and architecture. However, the relative extent to which shorter-term modulation and longer-term plasticity govern locomotor flexibility remains unclear. Here, we obtain simultaneously recorded kinematic and muscle activity data of fin and body musculature of an amphibious fish, Polypterus senegalus After examining swimming and walking behaviour in aquatically raised individuals, we show that walking behaviour is characterized by greater absolute duration of muscle activity in most muscles when compared with swimming, but that the magnitude of recruitment during walking is only increased in the secondary bursts of fin muscle and in the primary burst of the mid-body point. This localized increase in intensity suggests that walking in P. senegalus is powered in a few key locations on the fish, contrasting with the more distributed, low intensity muscle force that characterizes the stroke cycle during swimming. Finally, the increased intensity in secondary, but not primary, bursts of the fin muscles when walking probably underscores the importance of antagonistic muscle activity to prevent fin collapse, add stabilization and increase body support. Understanding the principles that underlie the flexibility of muscle function can provide key insights into the sources of animal functional and behavioural diversity.

Female striated urogenital sphincter contraction measured by shear wave elastography during pelvic floor muscle activation: Proof of concept and validation.

AIMS: Investigation of the function of the striated urogenital sphincter (SUS) is challenging because it is difficult to access and requires invasive measures. Ultrasound shear wave elastography (SWE) is a non-invasive real-time technique used to estimate tissue stiffness. As muscle stiffness can be used as an estimate of muscle force, SWE provides an opportunity to study contraction of the peri-urethral musculature. Validation of SWE to study SUS during functional tasks, such as pelvic floor muscle contractions, is required prior to application in clinical populations. METHODS: Ten healthy females (34[5] years) participated. Stiffness in a region expected to contain the SUS was quantified using SWE at rest and during a pelvic floor muscle contractions performed at 10%, 25%, and 50% of maximal voluntary contraction (MVC). Two repetitions were performed for 10 s. RESULTS: During contraction, stiffness increased in the region of the SUS in all participants and at all contraction intensities. Multiple regions of increased stiffness were detected, with 95.8% of regions situated ventral to the mid-urethra within the anatomical area of the SUS. The increase in stiffness was greater for 50% MVC than both 10% and 25% MVC contraction intensities (P < 0.01). CONCLUSIONS: Stiffness increased within the anatomical region of the SUS during voluntary pelvic floor muscle contractions with predictable response to changes in contraction intensity. These observations support the potential for ultrasound SWE to study SUS function non-invasively.

Independent evolution of striated muscles in cnidarians and bilaterians.

Striated muscles are present in bilaterian animals (for example, vertebrates, insects and annelids) and some non-bilaterian eumetazoans (that is, cnidarians and ctenophores). The considerable ultrastructural similarity of striated muscles between these animal groups is thought to reflect a common evolutionary origin. Here we show that a muscle protein core set, including a type II myosin heavy chain (MyHC) motor protein characteristic of striated muscles in vertebrates, was already present in unicellular organisms before the origin of multicellular animals. Furthermore, 'striated muscle' and 'non-muscle' myhc orthologues are expressed differentially in two sponges, compatible with a functional diversification before the origin of true muscles and the subsequent use of striated muscle MyHC in fast-contracting smooth and striated muscle. Cnidarians and ctenophores possess striated muscle myhc orthologues but lack crucial components of bilaterian striated muscles, such as genes that code for titin and the troponin complex, suggesting the convergent evolution of striated muscles. Consistently, jellyfish orthologues of a shared set of bilaterian Z-disc proteins are not associated with striated muscles, but are instead expressed elsewhere or ubiquitously. The independent evolution of eumetazoan striated muscles through the addition of new proteins to a pre-existing, ancestral contractile apparatus may serve as a model for the evolution of complex animal cell types.

What makes skeletal muscle striated? Discoveries in the endosarcomeric and exosarcomeric cytoskeleton.

One of the most iconic images in biology is the cross-striated appearance of a skeletal muscle fiber. The repeating band pattern shows that all of the sarcomeres are the same length. All of the A bands are the same length and are located in the middle of the sarcomeres. Furthermore, all of the myofibrils are transversely aligned across the muscle fiber. It has been known for 300 yr that skeletal muscle is striated, but only in the last 40 yr has a molecular understanding of the striations emerged. In the 1950s it was discovered that the extraction of myosin from myofibrils abolished the A bands, and the myofibrils were no longer striated. With the further extraction of actin, only the Z disks remained. Strangely, the sarcomere length did not change, and these "ghost" myofibrils still exhibited elastic behavior. The breakthrough came in the 1970s with the discovery of the gigantic protein titin. Titin, an elastic protein ~1 µm in length, runs from the Z disk to the middle of the A band and ensures that each sarcomere is the same length. Titin anchors the A band in the middle of the sarcomere and may determine thick-filament length and thus A-band length. In the 1970s it was proposed that the intermediate filament desmin, which surrounds the Z disks, connects adjacent myofibrils, resulting in the striated appearance of a skeletal muscle fiber.

Circular RNAs in Muscle Function and Disease.

Circular RNAs (circRNAs) are a class of RNA produced during pre-mRNA splicing that are emerging as new members of the gene regulatory network. In addition to being spliced in a linear fashion, exons of pre-mRNAs can be circularized by use of the 3' acceptor splice site of upstream exons, leading to the formation of circular RNA species. In this way, genetic information can be re-organized, increasing gene expression potential. Expression of circRNAs is developmentally regulated, tissue and cell-type specific, and shared across eukaryotes. The importance of circRNAs in gene regulation is now beginning to be recognized and some putative functions have been assigned to them, such as the sequestration of microRNAs or proteins, the modulation of transcription, the interference with splicing, and translation of small proteins. In accordance with an important role in normal cell biology, circRNA deregulation has been reported to be associated with diseases. Recent evidence demonstrated that circRNAs are highly expressed in striated muscle tissue, both skeletal and cardiac, that is also one of the body tissue showing the highest levels of alternative splicing. Moreover, initial studies revealed altered circRNA expression in diseases involving striated muscle, suggesting important functions of these molecules in the pathogenetic mechanisms of both heart and skeletal muscle diseases. The recent findings in this field will be described and discussed.