Skeletal Muscle最新文献

{"title":"Rapid restitution of contractile dysfunction by synthetic copolymers in dystrophin-deficient single live skeletal muscle fibers.","authors":"Dongwoo Hahn, Joseph D Quick, Brian R Thompson, Adelyn Crabtree, Benjamin J Hackel, Frank S Bates, Joseph M Metzger","doi":"10.1186/s13395-023-00318-y","DOIUrl":"10.1186/s13395-023-00318-y","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, a cytoskeletal protein essential for the preservation of the structural integrity of the muscle cell membrane. DMD patients develop severe skeletal muscle weakness, degeneration, and early death. We tested here amphiphilic synthetic membrane stabilizers in mdx skeletal muscle fibers (flexor digitorum brevis; FDB) to determine their effectiveness in restoring contractile function in dystrophin-deficient live skeletal muscle fibers. After isolating FDB fibers via enzymatic digestion and trituration from thirty-three adult male mice (9 C57BL10, 24 mdx), these were plated on a laminin-coated coverslip and treated with poloxamer 188 (P188; PEO₇₅-PPO₃₀-PEO₇₅; 8400 g/mol), architecturally inverted triblock (PPO₁₅-PEO₂₀₀-PPO₁₅, 10,700 g/mol), and diblock (PEO₇₅-PPO₁₆-C₄, 4200 g/mol) copolymers. We assessed the twitch kinetics of sarcomere length (SL) and intracellular Ca²⁺ transient by Fura-2AM by field stimulation (25 V, 0.2 Hz, 25 °C). Twitch contraction peak SL shortening of mdx FDB fibers was markedly depressed to 30% of the dystrophin-replete control FDB fibers from C57BL10 (P < 0.001). Compared to vehicle-treated mdx FDB fibers, copolymer treatment robustly and rapidly restored the twitch peak SL shortening (all P < 0.05) by P188 (15 μM =  + 110%, 150 μM =  + 220%), diblock (15 μM =  + 50%, 150 μM =  + 50%), and inverted triblock copolymer (15 μM =  + 180%, 150 μM =  + 90%). Twitch peak Ca²⁺ transient from mdx FDB fibers was also depressed compared to C57BL10 FDB fibers (P < 0.001). P188 and inverted triblock copolymer treatment of mdx FDB fibers increased the twitch peak Ca²⁺ transient (P < 0.001). This study shows synthetic block copolymers with varied architectures can rapidly and highly effectively enhance contractile function in live dystrophin-deficient skeletal muscle fibers.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"9"},"PeriodicalIF":4.9,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9649280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Myomaker and Myomerger in myofibers causes muscle pathology.","authors":"Phillip C Witcher, Chengyi Sun, Douglas P Millay","doi":"10.1186/s13395-023-00317-z","DOIUrl":"10.1186/s13395-023-00317-z","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle development and regeneration depend on cellular fusion of myogenic progenitors to generate multinucleated myofibers. These progenitors utilize two muscle-specific fusogens, Myomaker and Myomerger, which function by remodeling cell membranes to fuse to each other or to existing myofibers. Myomaker and Myomerger expression is restricted to differentiating progenitor cells as they are not detected in adult myofibers. However, Myomaker remains expressed in myofibers from mice with muscular dystrophy. Ablation of Myomaker from dystrophic myofibers results in reduced membrane damage, leading to a model where persistent fusogen expression in myofibers, in contrast to myoblasts, is harmful.</p><p><strong>Methods: </strong>Dox-inducible transgenic mice were developed to ectopically express Myomaker or Myomerger in the myofiber compartment of skeletal muscle. We quantified indices of myofiber membrane damage, such as serum creatine kinase and IgM⁺ myofibers, and assessed general muscle histology, including central nucleation, myofiber size, and fibrosis.</p><p><strong>Results: </strong>Myomaker or Myomerger expression in myofibers independently caused membrane damage at acute time points. This damage led to muscle pathology, manifesting with centrally nucleated myofibers and muscle atrophy. Dual expression of both Myomaker and Myomerger in myofibers exacerbated several aspects of muscle pathology compared to expression of either fusogen by itself.</p><p><strong>Conclusions: </strong>These data reveal that while myofibers can tolerate some level of Myomaker and Myomerger, expression of a single fusogen above a threshold or co-expression of both fusogens is damaging to myofibers. These results explain the paradigm that their expression in myofibers can have deleterious consequences in muscle pathologies and highlight the need for their highly restricted expression during myogenesis and fusion.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"8"},"PeriodicalIF":4.9,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9641751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New tools for the investigation of muscle fiber-type spatial distributions across histological sections.","authors":"Anna K Redmond,&nbsp;Tilman M Davies,&nbsp;Matthew R Schofield,&nbsp;Philip W Sheard","doi":"10.1186/s13395-023-00316-0","DOIUrl":"https://doi.org/10.1186/s13395-023-00316-0","url":null,"abstract":"<p><strong>Background: </strong>The functional and metabolic properties of skeletal muscles are partly a function of the spatial arrangement of fibers across the muscle belly. Many muscles feature a non-uniform spatial pattern of fiber types, and alterations to the arrangement can reflect age or disease and correlate with changes in muscle mass and strength. Despite the significance of this event, descriptions of spatial fiber-type distributions across a muscle section are mainly provided qualitatively, by eye. Whilst several quantitative methods have been proposed, difficulties in implementation have meant that robust statistical analysis of fiber type distributions has not yielded new insight into the biological processes that drive the age- or disease-related changes in fiber type distributions.</p><p><strong>Methods: </strong>We review currently available approaches for analysis of data reporting fast/slow fiber type distributions on muscle sections before proposing a new method based on a generalized additive model. We compare current approaches with our new method by analysis of sections of three mouse soleus muscles that exhibit visibly different spatial fiber patterns, and we also apply our model to a dataset representing the fiber type proportions and distributions of the mouse tibialis anterior.</p><p><strong>Results: </strong>We highlight how current methods can lead to differing interpretations when applied to the same dataset and demonstrate how our new method is the first to permit location-based estimation of fiber-type probabilities, in turn enabling useful graphical representation.</p><p><strong>Conclusions: </strong>We present an open-access online application that implements current methods as well as our new method and which aids the interpretation of a variety of statistical tools for the spatial analysis of muscle fiber distributions.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"7"},"PeriodicalIF":4.9,"publicationDate":"2023-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicle distribution and localization in skeletal muscle at rest and following disuse atrophy.","authors":"Ahmed Ismaeel, Douglas W Van Pelt, Zachary R Hettinger, Xu Fu, Christopher I Richards, Timothy A Butterfield, Jonathan J Petrocelli, Ivan J Vechetti, Amy L Confides, Micah J Drummond, Esther E Dupont-Versteegden","doi":"10.1186/s13395-023-00315-1","DOIUrl":"10.1186/s13395-023-00315-1","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle (SkM) is a large, secretory organ that produces and releases myokines that can have autocrine, paracrine, and endocrine effects. Whether extracellular vesicles (EVs) also play a role in the SkM adaptive response and ability to communicate with other tissues is not well understood. The purpose of this study was to investigate EV biogenesis factors, marker expression, and localization across cell types in the skeletal muscle. We also aimed to investigate whether EV concentrations are altered by disuse atrophy.</p><p><strong>Methods: </strong>To identify the potential markers of SkM-derived EVs, EVs were isolated from rat serum using density gradient ultracentrifugation, followed by fluorescence correlation spectroscopy measurements or qPCR. Single-cell RNA sequencing (scRNA-seq) data from rat SkM were analyzed to assess the EV biogenesis factor expression, and cellular localization of tetraspanins was investigated by immunohistochemistry. Finally, to assess the effects of mechanical unloading on EV expression in vivo, EV concentrations were measured in the serum by nanoparticle tracking analysis in both a rat and human model of disuse.</p><p><strong>Results: </strong>In this study, we show that the widely used markers of SkM-derived EVs, α-sarcoglycan and miR-1, are undetectable in serum EVs. We also found that EV biogenesis factors, including the tetraspanins CD63, CD9, and CD81, are expressed by a variety of cell types in SkM. SkM sections showed very low detection of CD63, CD9, and CD81 in myofibers and instead accumulation within the interstitial space. Furthermore, although there were no differences in serum EV concentrations following hindlimb suspension in rats, serum EV concentrations were elevated in human subjects after bed rest.</p><p><strong>Conclusions: </strong>Our findings provide insight into the distribution and localization of EVs in SkM and demonstrate the importance of methodological guidelines in SkM EV research.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"6"},"PeriodicalIF":4.9,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9999658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10391902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins.","authors":"Clothilde Claus,&nbsp;Moriya Slavin,&nbsp;Eugénie Ansseau,&nbsp;Céline Lancelot,&nbsp;Karimatou Bah,&nbsp;Saskia Lassche,&nbsp;Manon Fiévet,&nbsp;Anna Greco,&nbsp;Sara Tomaiuolo,&nbsp;Alexandra Tassin,&nbsp;Virginie Dudome,&nbsp;Benno Kusters,&nbsp;Anne-Emilie Declèves,&nbsp;Dalila Laoudj-Chenivesse,&nbsp;Baziel G M van Engelen,&nbsp;Denis Nonclercq,&nbsp;Alexandra Belayew,&nbsp;Nir Kalisman,&nbsp;Frédérique Coppée","doi":"10.1186/s13395-022-00310-y","DOIUrl":"https://doi.org/10.1186/s13395-022-00310-y","url":null,"abstract":"<p><strong>Background: </strong>We have previously demonstrated that double homeobox 4 centromeric (DUX4C) encoded for a functional DUX4c protein upregulated in dystrophic skeletal muscles. Based on gain- and loss-of-function studies we have proposed DUX4c involvement in muscle regeneration. Here, we provide further evidence for such a role in skeletal muscles from patients affected with facioscapulohumeral muscular dystrophy (FSHD).</p><p><strong>Methods: </strong>DUX4c was studied at RNA and protein levels in FSHD muscle cell cultures and biopsies. Its protein partners were co-purified and identified by mass spectrometry. Endogenous DUX4c was detected in FSHD muscle sections with either its partners or regeneration markers using co-immunofluorescence or in situ proximity ligation assay.</p><p><strong>Results: </strong>We identified new alternatively spliced DUX4C transcripts and confirmed DUX4c immunodetection in rare FSHD muscle cells in primary culture. DUX4c was detected in nuclei, cytoplasm or at cell-cell contacts between myocytes and interacted sporadically with specific RNA-binding proteins involved, a.o., in muscle differentiation, repair, and mass maintenance. In FSHD muscle sections, DUX4c was found in fibers with unusual shape or central/delocalized nuclei (a regeneration feature) staining for developmental myosin heavy chain, MYOD or presenting intense desmin labeling. Some couples of myocytes/fibers locally exhibited peripheral DUX4c-positive areas that were very close to each other, but in distinct cells. MYOD or intense desmin staining at these locations suggested an imminent muscle cell fusion. We further demonstrated DUX4c interaction with its major protein partner, C1qBP, inside myocytes/myofibers that presented features of regeneration. On adjacent muscle sections, we could unexpectedly detect DUX4 (the FSHD causal protein) and its interaction with C1qBP in fusing myocytes/fibers.</p><p><strong>Conclusions: </strong>DUX4c upregulation in FSHD muscles suggests it contributes not only to the pathology but also, based on its protein partners and specific markers, to attempts at muscle regeneration. The presence of both DUX4 and DUX4c in regenerating FSHD muscle cells suggests DUX4 could compete with normal DUX4c functions, thus explaining why skeletal muscle is particularly sensitive to DUX4 toxicity. Caution should be exerted with therapeutic agents aiming for DUX4 suppression because they might also repress the highly similar DUX4c and interfere with its physiological role.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"5"},"PeriodicalIF":4.9,"publicationDate":"2023-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9990282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9677989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An updated C. elegans nuclear body muscle transcriptome for studies in muscle formation and function.","authors":"Anna L Schorr,&nbsp;Alejandro Felix Mejia,&nbsp;Martina Y Miranda,&nbsp;Marco Mangone","doi":"10.1186/s13395-023-00314-2","DOIUrl":"https://doi.org/10.1186/s13395-023-00314-2","url":null,"abstract":"<p><p>The body muscle is an important tissue used in organisms for proper viability and locomotion. Although this tissue is generally well studied and characterized, and many pathways have been elucidated throughout the years, we still lack a comprehensive understanding of its transcriptome and how it controls muscle development and function. Here, we have updated a nuclear FACS sorting-based methodology to isolate and sequence a high-quality muscle transcriptome from Caenorhabditis elegans mixed-stage animals. We have identified 2848 muscle-specific protein-coding genes, including 78 transcription factors and 206 protein-coding genes containing an RNA binding domain. We studied their interaction network, performed a detailed promoter analysis, and identified novel muscle-specific cis-acting elements. We have also identified 16 high-quality muscle-specific miRNAs, studied their function in vivo using fluorochrome-based analyses, and developed a high-quality C. elegans miRNA interactome incorporating other muscle-specific datasets produced by our lab and others.Our study expands our understanding of how muscle tissue functions in C. elegans andin turn provides results that can in the future be applied to humans to study muscular-related diseases.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"4"},"PeriodicalIF":4.9,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9979539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9268856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiogenesis precedes myogenesis during regeneration following biopsy injury of skeletal muscle.","authors":"Nicole L Jacobsen,&nbsp;Aaron B Morton,&nbsp;Steven S Segal","doi":"10.1186/s13395-023-00313-3","DOIUrl":"https://doi.org/10.1186/s13395-023-00313-3","url":null,"abstract":"<p><strong>Background: </strong>Acute injury to skeletal muscle damages myofibers and fragment capillaries, impairing contractile function and local perfusion. Myofibers and microvessels regenerate from satellite cells and from surviving microvessel fragments, respectively, to restore intact muscle. Established models of injury have used myotoxins and physical trauma to demonstrate the concurrence of myogenesis and angiogenesis during regeneration. In these models, efferocytosis removes cellular debris while basal laminae persist to provide guidance during myofiber and microvessel regeneration. It is unknown whether the spatiotemporal coupling between myofiber and microvascular regeneration persists when muscle tissue is completely removed and local guidance cues are lost.</p><p><strong>Methods: </strong>To test whether complete removal of skeletal muscle tissue affects the spatiotemporal relationship between myogenesis and angiogenesis during regeneration, subthreshold volumetric muscle loss was created with a biopsy punch (diameter, 2 mm) through the center of the gluteus maximus (GM) in adult mice. Regeneration into the void was evaluated through 21 days post-injury (dpi). Microvascular perfusion was evaluated in vivo by injecting fluorescent dextran into the circulation during intravital imaging. Confocal imaging and histological analyses of whole-mount GM preparations and tissue cross-sections assessed the growth of microvessels and myofibers into the wound.</p><p><strong>Results: </strong>A provisional matrix filled with PDGFRα⁺ and CD45⁺ cells spanned the wound within 1 dpi. Regenerating microvessels advanced from the edges of the wound into the matrix by 7 dpi. Nascent microvascular networks formed by 10 dpi with blood-perfused networks spanning the wound by 14 dpi. In striking contrast, the wound remained devoid of myofibers at 7 and 10 dpi. Myogenesis into the wound was apparent by 14 dpi and traversed the wound by 21 dpi. Regenerated myofibers and microvessels were disorganized compared to the uninjured muscle.</p><p><strong>Conclusions: </strong>Following punch biopsy of adult skeletal muscle, regenerating microvessels span the wound and become perfused with blood prior to myofiber regeneration. The loss of residual guidance cues with complete tissue removal disrupts the spatiotemporal correspondence between microvascular and myofiber regeneration. We conclude that angiogenesis precedes myogenesis during regeneration following subthreshold volumetric muscle loss.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"3"},"PeriodicalIF":4.9,"publicationDate":"2023-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9551224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sarcopenia: investigation of metabolic changes and its associated mechanisms.","authors":"Jair Marques,&nbsp;Engy Shokry,&nbsp;Olaf Uhl,&nbsp;Lisa Baber,&nbsp;Fabian Hofmeister,&nbsp;Stefanie Jarmusch,&nbsp;Martin Bidlingmaier,&nbsp;Uta Ferrari,&nbsp;Berthold Koletzko,&nbsp;Michael Drey","doi":"10.1186/s13395-022-00312-w","DOIUrl":"https://doi.org/10.1186/s13395-022-00312-w","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform.</p><p><strong>Methods: </strong>Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed.</p><p><strong>Results: </strong>Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome.</p><p><strong>Conclusions: </strong>We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"2"},"PeriodicalIF":4.9,"publicationDate":"2023-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9850598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10698115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis of sarcospan overexpression in mdx skeletal muscle reveals compensatory remodeling of cytoskeleton-matrix interactions that promote mechanotransduction pathways.","authors":"Jackie L McCourt, Kristen M Stearns-Reider, Hafsa Mamsa, Pranav Kannan, Mohammad Hossein Afsharinia, Cynthia Shu, Elizabeth M Gibbs, Kara M Shin, Yerbol Z Kurmangaliyev, Lauren R Schmitt, Kirk C Hansen, Rachelle H Crosbie","doi":"10.1186/s13395-022-00311-x","DOIUrl":"10.1186/s13395-022-00311-x","url":null,"abstract":"<p><strong>Background: </strong>The dystrophin-glycoprotein complex (DGC) is a critical adhesion complex of the muscle cell membrane, providing a mechanical link between the extracellular matrix (ECM) and the cortical cytoskeleton that stabilizes the sarcolemma during repeated muscle contractions. One integral component of the DGC is the transmembrane protein, sarcospan (SSPN). Overexpression of SSPN in the skeletal muscle of mdx mice (murine model of DMD) restores muscle fiber attachment to the ECM in part through an associated increase in utrophin and integrin adhesion complexes at the cell membrane, protecting the muscle from contraction-induced injury. In this study, we utilized transcriptomic and ECM protein-optimized proteomics data sets from wild-type, mdx, and mdx transgenic (mdx^TG) skeletal muscle tissues to identify pathways and proteins driving the compensatory action of SSPN overexpression.</p><p><strong>Methods: </strong>The tibialis anterior and quadriceps muscles were isolated from wild-type, mdx, and mdx^TG mice and subjected to bulk RNA-Seq and global proteomics analysis using methods to enhance capture of ECM proteins. Data sets were further analyzed through the ingenuity pathway analysis (QIAGEN) and integrative gene set enrichment to identify candidate networks, signaling pathways, and upstream regulators.</p><p><strong>Results: </strong>Through our multi-omics approach, we identified 3 classes of differentially expressed genes and proteins in mdx^TG muscle, including those that were (1) unrestored (significantly different from wild type, but not from mdx), (2) restored (significantly different from mdx, but not from wild type), and (3) compensatory (significantly different from both wild type and mdx). We identified signaling pathways that may contribute to the rescue phenotype, most notably cytoskeleton and ECM organization pathways. ECM-optimized proteomics revealed an increased abundance of collagens II, V, and XI, along with β-spectrin in mdx^TG samples. Using ingenuity pathway analysis, we identified upstream regulators that are computationally predicted to drive compensatory changes, revealing a possible mechanism of SSPN rescue through a rewiring of cell-ECM bidirectional communication. We found that SSPN overexpression results in upregulation of key signaling molecules associated with regulation of cytoskeleton organization and mechanotransduction, including Yap1, Sox9, Rho, RAC, and Wnt.</p><p><strong>Conclusions: </strong>Our findings indicate that SSPN overexpression rescues dystrophin deficiency partially through mechanotransduction signaling cascades mediated through components of the ECM and the cortical cytoskeleton.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"1"},"PeriodicalIF":5.3,"publicationDate":"2023-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9817407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10134465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The prevalence of low muscle mass associated with obesity in the USA.","authors":"Dana J Murdock,&nbsp;Ning Wu,&nbsp;Joseph S Grimsby,&nbsp;Roberto A Calle,&nbsp;Stephen Donahue,&nbsp;David J Glass,&nbsp;Mark W Sleeman,&nbsp;Robert J Sanchez","doi":"10.1186/s13395-022-00309-5","DOIUrl":"https://doi.org/10.1186/s13395-022-00309-5","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia is defined as age-related low muscle mass and function, and can also describe the loss of muscle mass in certain medical conditions, such as sarcopenic obesity. Sarcopenic obesity describes loss of muscle and function in obese individuals; however, as sarcopenia is an age-related condition and obesity can occur in any age group, a more accurate term is obesity with low lean muscle mass (OLLMM). Given limited data on OLLMM (particularly in those aged < 65 years), the purpose of this study was to estimate the prevalence of OLLMM in adults aged ≥ 20 years in the USA.</p><p><strong>Methods: </strong>Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and 1999-2006 were used. OLLMM was defined as an appendicular lean mass, adjusted for body mass index (BMI), cut-off point < 0.789 for males and < 0.512 for females, measured by dual-energy X-ray absorptiometry (DXA). DXA was only measured in individuals 20-59 years old in NHANES 2017-2018; we therefore utilized logistic regression models to predict OLLMM from NHANES 1999-2006 for those aged ≥ 60 years. The prevalence of OLLMM was estimated overall, and by sex, age, race/ethnicity, and clinical subgroup (high BMI, prediabetes, type 2 diabetes mellitus [T2DM], non-alcoholic fatty liver disease [NAFLD] with fibrosis, or post-bariatric surgery). Prevalence estimates were extrapolated to the USA population using NHANES sampling weights.</p><p><strong>Results: </strong>We estimated that, during 2017-2018, 28.7 million or 15.9% of the USA population had OLLMM. The prevalence of OLLMM was greater in older individuals (8.1%, aged 20-59 years vs 28.3%, aged ≥ 60 years), highest (66.6%) in Mexican-American females aged ≥ 60 years, and lowest (2.6%) in non-Hispanic Black males aged 20-59 years. There was a higher prevalence of OLLMM in adults with prediabetes (19.7%), T2DM (34.5%), NAFLD with fibrosis (25.4%), or post-bariatric surgery (21.8%), compared with those without each condition.</p><p><strong>Conclusions: </strong>Overall, the burden of OLLMM in the USA is substantial, affecting almost 30 million adults. The prevalence of OLLMM increased with age, and among those with prediabetes, T2DM, NAFLD with fibrosis, or post-bariatric surgery. A unified definition of OLLMM will aid diagnosis and treatment strategies.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"12 1","pages":"26"},"PeriodicalIF":4.9,"publicationDate":"2022-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9769063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10579759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}