Many organs of the body are susceptible to cancer development. However, striated muscles-which include skeletal and cardiac muscles-are rarely the sites of primary cancers. Most deaths from cancer arise due to complications associated with the development of secondary metastatic tumours, for which there are few effective therapies. However, as with primary cancers, the establishment of metastatic tumours in striated muscle accounts for a disproportionately small fraction of secondary tumours, relative to the proportion of body composition. Examining why primary and metastatic cancers are comparatively rare in striated muscle presents an opportunity to better understand mechanisms that can influence cancer cell biology. To gain insights into the incidence and distribution of muscle metastases, this review presents a definitive summary of the 210 case studies of metastasis in muscle published since 2010. To examine why metastases rarely form in muscles, this review considers the mechanisms currently proposed to render muscle an inhospitable environment for cancers. The \"seed and soil\" hypothesis proposes that tissues\' differences in susceptibility to metastatic colonization are due to differing host microenvironments that promote or suppress metastatic growth to varying degrees. As such, the \"soil\" within muscle may not be conducive to cancer growth. Gaining a greater understanding of the mechanisms that underpin the resistance of muscles to cancer may provide new insights into mechanisms of tumour growth and progression, and offer opportunities to leverage insights into the development of interventions with the potential to inhibit metastasis in susceptible tissues.

Striated muscle insertions into the skin and mucosa are present in the head, neck, and pelvic floor. We reexamined the histology of these tissues to elucidate their role in transmission of the force. We examined histological sections of 25 human fetuses (gestational ages of ~11-19 weeks and ~26-40 weeks) and 6 cadavers of elderly individuals. Facial muscle insertion or terminal almost always formed as an interdigitation with another muscle or as a circular arrangement in which muscle fiber insertions were sandwiched and mechanically supported by other muscle fibers (like an in-series muscle). Our examination of the face revealed some limited exceptions in which muscle fibers that approached the dermis were always in the nasalis and mentalis muscles, and often in the levator labii superioris alaeque nasi muscle. The buccinator muscle was consistently inserted into the basement membrane of the oral mucosa. Parts of the uvulae muscle in the soft palate and of the intrinsic vertical muscle of the tongue were likely to direct toward the mucosa. In contrast, the pelvic floor did not contain striated muscle fibers that were directed toward the skin or mucosa. Although \'cutaneous muscle\' is a common term, the actual insertion of a muscle into the skin or mucosa seemed to be very rare. Instead, superficial muscle insertion often consisted of interdigitated muscle bundles that had different functional vectors. In this case, the terminal of one muscle bundle was sandwiched and fixed mechanically by other bundles.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been especially devastating to patients with comorbidities, including metabolic and cardiovascular diseases. Elevated blood glucose during SARS-CoV-2 infection increased mortality of patients with COVID-19, although the mechanisms are not well understood. It has been previously demonstrated that glucose transport and utilization is a crucial pathway for other highly infectious RNA viruses. Thus, we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole body glucose metabolism. Specific pathogen-free domestic cats were intratracheally inoculated with USA-WA1/2020 (wild-type) SARS-CoV-2 or vehicle-inoculated, then euthanized at 4- and 8-days postinoculation (dpi). Blood glucose and cortisol concentrations were elevated at 4 and 8 dpi. Blood ketones, insulin, and angiotensin II concentrations remained unchanged throughout the experimental timeline. SARS-CoV-2 RNA was detected in the lung and heart, without changes in angiotensin-converting enzyme 2 (ACE2) RNA expression. In the lung, SARS-CoV-2 infection increased glucose transporter 1 (GLUT1) protein levels at 4 and 8 dpi, whereas GLUT4 level was only upregulated at 8 dpi. In the heart, GLUT-1 and -4 protein levels remained unchanged. Furthermore, GLUT1 level was upregulated in the skeletal muscle at 8 dpi, and AMPK was activated in the hearts of infected cats. SARS-CoV-2 infection increased blood glucose concentration and pulmonary GLUT protein levels. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming primarily in the lung to support viral replication. Furthermore, this translational feline model mimicked human COVID-19 and could be used to explore novel therapeutic targets to treat metabolic disease during SARS-CoV-2 infection.NEW & NOTEWORTHY Our study on a feline model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, mirroring human COVID-19, revealed alterations in whole body and cellular glucose metabolism. Infected cats developed mild hyperglycemia, increased protein levels of glucose transporters in the lung, and AMPK activation in the heart. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming in the cardiorespiratory system to support viral replication. Understanding these mechanisms could lead to novel antiviral therapeutic strategies.

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The M-line of striated muscle is a complex structure that anchors myosin-containing thick filaments and also participates in signaling and proteostasis. While the physical associations among many M-line components have been defined, the mechanism of thick filament attachment is not completely understood. In Caenorhabditis elegans, myosin A is essential for viability and forms the site of M-line attachment at the center of the filament, whereas myosin B forms the filament arms. Using a mutant myosin A that forms ectopic filaments, we examined interactions between myosin A and M-line proteins in intact muscle cells. Ectopic myosin A recruits the giant kinase UNC-89/obscurin, a presumed scaffolding protein, in an interaction that requires the zinc-finger protein UNC-98, but not UNC-82/NUAK, UNC-97/PINCH, or UNC-96. In myosin A mutants, UNC-89/obscurin patterning is highly defective in embryos and adults. A chimeric myosin containing 169 residues of the myosin A C-terminal rod, coincident with the UNC-98/ZnF binding site, is sufficient for colocalization of UNC-89/obscurin and UNC-98/ZnF in M-line structures whereas a myosin chimera lacking these residues colocalizes with UNC-89/obscurin in M-lines that lack UNC-98. Thus, at least two myosin A rod regions contribute independently to M-line organization. We hypothesize that these M-line-organizing functions correspond to the essential \"filament initiation function\" performed by this isoform.

Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological requirements. Changes in calcium concentration regulate the thin filament activation. A separate but linked mechanism regulates the thick filament activation, which frees sufficient myosin heads to bind the thin filament, thereby producing the required force. Thick filaments contain additional nonmyosin proteins, myosin-binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3-D image reconstruction of frozen-hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429Å repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin-binding protein C. We think that this hierarchy of control explains many of the effects of length-dependent activation as well as stretch activation in cardiac muscle control.

Synaptopodin-2 (SYNPO2) is a protein associated with the Z-disc in striated muscle cells. It interacts with α-actinin and filamin C, playing a role in Z-disc maintenance under stress by chaperone-assisted selective autophagy (CASA). In smooth muscle cells, SYNPO2 is a component of dense bodies. Furthermore, it has been proposed to play a role in tumor cell proliferation and metastasis in many different kinds of cancers. Alternative transcription start sites and alternative splicing predict the expression of six putative SYNPO2 isoforms differing by extended amino- and/or carboxy-termini. Our analyses at mRNA and protein levels revealed differential expression of SYNPO2 isoforms in cardiac, skeletal and smooth muscle cells. We identified synemin, an intermediate filament protein, as a novel binding partner of the PDZ-domain in the amino-terminal extension of the isoforms mainly expressed in cardiac and smooth muscle cells, and demonstrated colocalization of SYNPO2 and synemin in both cell types. A carboxy-terminal extension, mainly expressed in smooth muscle cells, is sufficient for association with dense bodies and interacts with α-actinin. SYNPO2 therefore represents an additional and novel link between intermediate filaments and the Z-discs in cardiomyocytes and dense bodies in smooth muscle cells, respectively. In pathological skeletal muscle samples, we identified SYNPO2 in the central and intermediate zones of target fibers of patients with neurogenic muscular atrophy, and in nemaline bodies. Our findings help to understand distinct functions of individual SYNPO2 isoforms in different muscle tissues, but also in tumor pathology.

The mechanisms that ensure proper assembly, activity, and turnover of myosin II filaments are fundamental to a diverse range of cellular processes. In Caenorhabditis elegans striated muscle, thick filaments contain two myosins that are functionally distinct and spatially segregated. Using transgenic double mutants, we demonstrate that the ability of increased myosin A expression to restore muscle structure and movement in myosin B mutants requires UNC-82/NUAK kinase activity. Myosin B function appears unaffected in the kinase-impaired unc-82(e1220) mutant: the recessive antimorphic effects on early assembly of paramyosin and myosin A in this mutant are counteracted by increased myosin B expression and exacerbated by loss of myosin B. Using chimeric myosins and motility assays, we mapped the region of myosin A that requires UNC-82 activity to a 531-amino-acid region of the coiled-coil rod. This region includes the 264-amino-acid Region 1, which is sufficient in chimeric myosins to rescue the essential filament-initiation function of myosin A, as well as two sites that interact with myosin head domains in the Interacting Heads Motif. A specific physical interaction between myosin A and UNC-82::GFP is supported by GFP labeling of ectopic myosin A filaments but not thin filaments. We hypothesize that UNC-82 regulates assembly competence of myosin A during parallel assembly in the filament arms.

This study aims to activate the external urethral sphincter (EUS), which plays a critical role in micturition control, through optogenetics and to determine its potential contribution to the stabilization of sensitized micturition activity. The viral vector (AAV2/8-CMV-hChR2(H134R)-EGFP) is utilized to introduce light-gated ion channels (hChR2/H134R) into the EUS of wild-type C57BL/6 mice. Following the induction of sensitized micturition activity using weak acetic acid (0.1%) in anesthetized mice, optical stimulation of the EUS muscle tissue expressing channel rhodopsin is performed using a 473 nm laser light delivered through optical fibers, and the resulting changes in muscle activation and micturition activity are examined. Through EMG (electromyography) measurements, it is confirmed that optical stimulation electrically activates the EUS muscle in mice. Analysis of micturition activity using cystometry reveals a 70.58% decrease in the micturition period and a 70.27% decrease in the voiding volume due to sensitized voiding. However, with optical stimulation, the micturition period recovers to 101.49%, and the voiding volume recovered to 100.22%. Stimulation of the EUS using optogenetics can alleviate sensitized micturition activity and holds potential for application in conjunction with other micturition control methods.

Striated muscle thick filaments are composed of myosin II and several non-myosin proteins which define the filament length and modify its function. Myosin II has a globular N-terminal motor domain comprising its catalytic and actin-binding activities and a long α-helical, coiled tail that forms the dense filament backbone. Myosin alone polymerizes into filaments of irregular length, but striated muscle thick filaments have defined lengths that, with thin filaments, define the sarcomere structure. The motor domain structure and function are well understood, but the myosin filament backbone is not. Here we report on the structure of the flight muscle thick filaments from Drosophila melanogaster at 4.7 Å resolution, which eliminates previous ambiguities in non-myosin densities. The full proximal S2 region is resolved, as are the connecting densities between the Ig domains of stretchin-klp. The proteins, flightin, and myofilin are resolved in sufficient detail to build an atomic model based on an AlphaFold prediction. Our results suggest a method by which flightin and myofilin cooperate to define the structure of the thick filament and explains a key myosin mutation that affects flightin incorporation. Drosophila is a genetic model organism for which our results can define strategies for functional testing.