Eric N. Olson

Annexins cooperate with Myomaker to promote myoblast fusion

Myoblast fusion is essential for skeletal muscle development and regeneration. Myomaker is a muscle-specific fusogen indispensable for this process. Cryoelectron microscopy analysis has shown that Myomaker dimerization is required for myoblast fusion and muscle formation. However, the precise molecular mechanisms of Myomaker function remain unclear. Notably, the short extracellular domain of Myomaker suggests the involvement of additional proteins that cooperate with Myomaker to facilitate membrane fusion. To identify potential interacting partners of Myomaker, we employed an APEX2-based proximity labeling approach in a synchronized myoblast fusion and differentiation system. By comparing results with a fusion-deficient mutant form of Myomaker, we identified several members of the Annexin family of calcium-dependent phospholipid-binding proteins as prominent candidates for interaction, particularly under prefusion conditions. Among these, Annexins A2, A5, and A6 were found to colocalize with Myomaker at the myoblast plasma membrane. Proximity ligation assays further confirmed the close association of these Annexins with Myomaker at the cell surface. Functional analyses demonstrated that these Annexins can promote heterologous cell–cell fusion between fibroblasts and myoblasts. While single knockdown of Annexin A2, A5, or A6 had minimal effects, the simultaneous knockdown of all three impaired myoblast fusion, indicating functional redundancy among them. Together, these findings indicate that Annexins A2, A5, and A6 cooperate with Myomaker to promote myoblast fusion, providing a mechanistic link between the fusogenic machinery and membrane dynamics during myoblast fusion.

KDM inhibition with JIB-04 prevents sudden cardiac death and preserves function in preclinical HCM.

Depleting γδ T cells or IL-17A impairs neonatal cardiac regeneration and worsens post-MI fibrosis.

Genetic and regenerative contexts specify distinct soft tissue sarcoma identities from Twist2+ progenitors

Soft tissue sarcomas (STS) comprise diverse mesenchymal malignancies whose developmental origins and mechanisms of subtype specification remain poorly understood. Whether distinct sarcoma subtypes can arise from a common progenitor through distinct oncogenic and tissue contexts has remained unresolved. Here, we show that skeletal muscle progenitors marked by expression of the Twist2 transcription factor generate distinct STS subtypes in response to defined genetic and microenvironmental cues. Activation of Kras together with Trp53 loss maintained a mesenchymal cell identity and drove highly penetrant undifferentiated pleomorphic sarcoma (UPS), whereas Trp53 loss or Hedgehog pathway activation in regenerating skeletal muscle preferentially induced fusion-negative rhabdomyosarcoma (FN-RMS). Single-nucleus RNA sequencing revealed fundamentally distinct tumor cell-state landscapes, with UPS enriched for mesenchymal-like states and FN-RMS spanning a continuum of myogenic differentiation states. Comparative analysis demonstrated that both models faithfully recapitulate the cellular hierarchies observed in their respective human STS subtypes. These findings reveal how oncogenic and microenvironmental contexts direct malignant lineage identity from a shared progenitor, providing a powerful platform for defining the developmental mechanisms and therapeutic vulnerabilities underlying STS subtype specification.

Myogenic Fusogen‐Engineered Lipid Nanoparticles Enhance mRNA Delivery in Skeletal Muscle

SmallCirculation

Targeting microRNAs emerges as a promising therapeutic strategy across various cardiovascular diseases.

CRISPR-Cas9 base editing shows therapeutic promise in heart failure by modulating key signaling pathways.

A human cardiomyocyte screen identifies optimized lipid nanoparticles for in vivo cardiac gene editing

Nrf1 coordinates proteasome activity and autophagy to maintain cardiac proteostasis

Muscle Iron Overload Contributes to Cancer Cachexia-Induced Muscle Wasting

Infrared Thermal Imaging Enhanced Selection Intensity for Fusarium Head Blight Resistance in Soft Winter Wheat

Modulation of the JAK2-STAT3 pathway promotes expansion and maturation of human iPSC-derived myogenic progenitor cells

Generation of in vitro human induced pluripotent cell (hiPSC)-derived skeletal muscle progenitor cells (SMPCs) holds great promise for regenerative medicine for skeletal muscle wasting diseases, for example Duchenne muscular dystrophy (DMD). While multiple approaches have been described to obtain SMPCs in vitro , hiPSC-derived SMPCs generated using transgene-free protocols are usually obtained in a low amount and resemble a more embryonal/fetal stage of differentiation. Here, we demonstrate that modulation of the JAK2/STAT3 signaling pathway during an in vitro skeletal muscle differentiation protocol increases the yield of PAX7 + and CD54 + human SMPCs (hSMPCs) and drives them to a higher maturation stage, in both human embryonic stem (ES) and patient-derived induced pluripotent cells (iPSCs). Importantly, the obtained SMPCs are able to differentiate into multinucleated myotubes in vitro and engraft in vivo . These findings reveal that modulation of the JAK2/STAT3 signaling pathway is a potential therapeutic avenue to generate SMPCs in vitro with potential for cell therapy approaches.

Precise gene editing of pathogenic Lamin A mutations corrects cardiac disease

Engineering a serum response factor superactivator of smooth muscle gene expression with a condensate-forming domain

Gene Editing Applications as Future Cardiovascular Therapies

PHF7 delivery drives cardiomyocyte reprogramming and improves post-infarction survival and function in mice.

A mechanistic basis of fast myofiber vulnerability to neuromuscular diseases

Neuromuscular diseases such as amyotrophic lateral sclerosis and sarcopenia cause muscle atrophy, which preferentially affects fast-twitch glycolytic myofibers. The mechanisms underlying the susceptibility of fast myofibers to disease remain unclear. To investigate this, we analyzed the transcriptional profiles of myonuclei from denervated muscle fibers. We found that the fast muscle gene program and the transcription factor Maf were repressed upon denervation. Overexpression of Maf in mice prevented loss of muscle mass caused by denervation by repressing atrophic genes and restoring fast gene expression. Similar repression of fast genes and Maf was observed in muscles from mice and humans with amyotrophic lateral sclerosis. Notably, Maf overexpression in human skeletal muscle cells in vitro prevented muscle atrophy and activated the expression of fast muscle genes. Our findings highlight a key role for Maf in maintaining muscle mass and could offer a promising therapeutic strategy to preserve muscle function during disease, aging, and injury.

Adenine base editing rescues smooth muscle dysfunction and prevents pathogenic vascular remodeling in ACTA2-mutant mice.

Optimized genomic editing of a common Duchenne muscular dystrophy mutation in patient-derived muscle cells and a new humanized mouse model

Cas9)-LRVQR to restore dystrophin expression in patient-derived induced pluripotent stem cells (iPSCs) and a newly generated humanized DMD mouse model. We compared two injection routes for adeno-associated virus (AAV) serotype 9 to deliver gene-editing components to neonatal mice: intraperitoneal (IP) and facial vein (FV) injection. We observed efficient restoration of dystrophin protein expression across multiple skeletal muscle groups and the heart. The AAV9-mediated CRISPR single-cut approach ameliorated key DMD hallmarks, including histopathological phenotypes, impaired grip strength, and elevated serum creatine kinase levels. Our optimized strategies for dystrophin restoration in humanized DMD mice with exon 52 deletion represent a promising treatment for DMD.

SARS-CoV-2 humoral immune responses in convalescent individuals over 12 months reveal severity-dependent antibody dynamics

Defining the kinetics of SARS-CoV-2 antibody responses is critical for informing the management of reinfections, vaccinations, and therapeutics of Coronavirus disease 2019 (COVID-19). Using four antibody assays, we evaluated antibody titers against SARS-CoV-2 nucleocapsid (N), spike (S), and receptor binding domain (RBD) in 98 convalescent participants with varying COVID-19 disease severities (asymptomatic, mild, moderate or severe) at 1, 3, 6, and 12-months post-SARS-CoV-2-positive PCR and in 17 non-vaccinated, non-infected controls. Increasing acute COVID-19 disease severity correlates with higher anti-N and anti-RBD titers throughout 12 months post-infection. Anti-N and anti-RBD titers decline over time in all participants, except for increased anti-RBD titers post-vaccination, with hospitalized participants exhibiting faster decay rates. Less than 50% of participants retain anti-N titers above controls at 12 months, with non-hospitalized participants falling below controls sooner. Nearly all participants maintain anti-RBD titers above controls for 12 months, suggesting long-term protection against severe reinfections. Nonetheless, by 6 months, few participants retain >50% of their initial 1-month anti-N or anti-RBD titers. Notably, vaccine-induced anti-RBD titers are higher in non-hospitalized participants. Lastly, early convalescent titers correlate with age but not with Post-Acute Sequelae of SARS-CoV-2 infection (PASC) status or steroid use. Hospitalized participants initially develop higher anti-SARS-CoV-2 antibody titers that decline faster relative to non-hospitalized participants. While anti-N titers fall below control levels in some participants, anti-RBD titers remain above controls over 12 months, demonstrating long-lived antibody responses known to protect against severe disease. These findings advance our understanding of COVID-19 antibody dynamics. This study explores how the immune system responds to COVID-19 over time by measuring antibodies, small proteins that help fight infection. We studied 98 participants who recovered from COVID-19 with varying illness severities and 17 who were never infected. Blood samples were collected over a year to track changes in antibody levels. Our results show that severe illness leads to higher antibody levels, though with a more precipitous antibody decline than in milder cases. Notably, antibodies that offer long-term protection against severe COVID-19 remain high for 12 months after the infection in most individuals. Lastly, vaccination boosts antibody levels, particularly in individuals with milder illness. Our research enhances understanding of immunity post COVID-19 and informs vaccination and reinfection prevention strategies. Siles Alvarado and Schuler et al. examine the long-term dynamics of SARS-CoV-2 antibodies in individuals with varying COVID-19 severities over 12 months. While anti-N antibodies decline, anti-RBD antibodies persist, offering insights into the evolving immunity post-COVID.