Skeletal muscle plays a vital role in voluntary movement and locomotion. Fast-twitch muscle fibres are characterized by their rapid contraction kinetics, high-force generation and a distinct gene expression profile compared to slow-twitch fibres. These fibres have a predominant expression of fast skeletal myosin binding protein-C (fMyBP-C). The role of fMyBP-C in skeletal muscle disease and aging remains poorly understood. To address this, our study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology.
Skeletal muscle samples from wild-type, db/db, MDX and ECC injury model (2-7 months) were analysed to determine the fMyBP-C levels. Next, male Mybpc2 knockout (C2-/-) mice, both young (3-5 months) and old (22 months), were utilized to investigate the role of fMyBP-C in aging. The effects of C2-/- and aging on the fibre type, size and number, as well as the overall muscle structure, were evaluated using immunohistochemistry and electron microscopy. In vivo and ex vivo muscle force generation was assessed to determine the functional impact of C2-/- and aging. RNA sequencing was conducted to identify the altered molecular pathways causing the muscle dysfunction in young and old C2-/- mice.
The expression of fMyBP-C was reduced (0.25-fold, p < 0.05) in the fast-twitch muscles of db/db mice, with a modest compensatory upregulation of slow skeletal MyBP-C (sMyBP-C) (~1.15-fold, p < 0.05). In MDX mice, fMyBP-C levels remain unchanged, whereas sMyBP-C levels were upregulated (~1.2-fold, p < 0.01). The fMyBP-C expression was 75% higher in the male skeletal muscles (p < 0.01) compared to females. Studies in young male C2-/- mice revealed a reduction in isometric tetanic force generation by 25% (p < 0.01) and relaxation rate by 42% (p < 0.001). The C2-/- mice also had 12.8% fewer type IIb fibres (p < 0.01), and a 20% reduction in type IIb fibre size (p < 0.01). Similarly, aged male C2-/- mice exhibited significant deficits in muscle strength, endurance and survival rate relative to their wild-type counterparts. The aged male C2-/- mice displayed a reduced size of type IIa, IIx and IIb muscle fibres compared to aged wild-type mice. RNA sequencing revealed that assembly and trimerization of collagen fibril pathway-related genes were altered in C2-/- mice.
fMyBP-C is a critical regulator of muscle function and homeostasis in young male fast-twitch muscle fibres. Its absence exacerbates the impact of aging on muscle structure and function. These findings suggest that fMyBP-C could serve as a promising therapeutic target for mitigating muscle wasting associated with aging and disease.
© 2025 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.

Background Skeletal muscle plays a vital role in voluntary motion and locomotion. Fast-twitch muscle fibers are characterized by their rapid contraction kinetics, high force generation capacity, and a distinct gene expression profile compared to slow-twitch fibers. Skeletal myosin binding protein-C (MyBP-C) paralogs, slow (sMyBP-C) and fast (fMyBP-C), interact with myosin and actin filaments within sarcomeres to modulate force development during contraction. These paralogs are differentially expressed in muscle fibers, with fMyBP-C predominantly expressed in the fast-twitch fibers. However, the role of fMyBP-C in skeletal muscle disease states and aging remains poorly understood. This study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology. Methods Adult skeletal muscle samples aged 2∼7 months from male and female wild-type, db/db, MDX, ECC injury model, were used to determine the differential expression of fMyBP-C. Next, Mybpc2 knockout (C2 -/- ) young (3∼5 months) and old (22 months) male mice were used to define the role of fMyBP-C in aging. Western immunoblotting was employed to analyze the expression of fMyBP-C and sMyBP-C and the phosphorylation status of sMyBP-C. The impact of C2 -/- and aging on the fiber type, size, and number as well as general muscle structure was assessed by immunohistochemistry and electron microscopy. The functional effect of C2 -/- and aging was measured in terms of in vivo and ex vivo muscle force generation. Lastly, RNA sequencing was performed to identify the molecular pathways dysregulated in the C2 -/- mediated muscle dysfunction in young and old mice. Results fMyBP-C was significantly reduced with a modest compensatory upregulation of sMyBP-C in the diseased fast-twitch muscles. fMyBP-C has a significantly higher expression in the male skeletal muscles compared to females. Further studies using young male C2 -/- mice showed a significant reduction in isometric tetanic force generation and relaxation rate, fiber type switching, atrophy, and altered gene expressions related to muscle function and metabolism compared to wild-type mice. Similarly, compared to their wild-type counterparts, aged male C2 -/- mice display significant deficits in muscle strength, endurance, and survival rate, accompanied by changes in muscle fiber size and molecular signaling pathways critical for muscle homeostasis. Conclusion fMyBP-C is an important regulator of muscle function and homeostasis in young and aged male fast-twitch muscle fibers. The absence of fMyBP-C aggravates the effect of aging on muscle structure and function. fMyBP-C has the potential to be a therapeutic target to modulate muscle wasting caused by aging and disease.

A20-binding inhibitor of NF-κB activation (ABIN1) is a polyubiquitin-binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin-binding site (Abin1Q478H/Q478H ) is generated. These mice develop MDS-like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H cells are sensitive to RIPK1 kinase-RIPK3-MLKL-dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase-dead mutation. This indicates that the necroptosis-independent function of RIPK3 is critical for anemia development in Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H mice exhibit higher levels of type I interferon (IFN-I) expression in bone marrow cells compared towild-type mice. Consistently, blocking type I IFN signaling through the co-deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.
© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Disordered immune responses and cholesterol metabolism have been implicated in age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals. SULT2B1, the key enzyme of sterol sulfonation, plays important roles in inflammation and cholesterol metabolism. However, the role and underlying mechanism of SULT2B1 in AMD have not been investigated thus far. Here, we report that SULT2B1 is specifically expressed in macrophages in choroidal neovascularization lesions. Sutl2b1 deficiency significantly reduced leakage areas and inhibited pathological angiogenesis by inhibiting M2 macrophage activation in vivo and in vitro. Mechanistically, loss of Sult2b1 activated LXRs and subsequently increased ABCA1 and ABCG1 (ABCA1/G1)-mediated cholesterol efflux from M2 macrophages. LXR inhibition (GSK2033 treatment) in Sult2b1 -/- macrophages reversed M2 polarization and decreased intracellular cholesterol capacity to promote pathological angiogenesis. In contrast to SULT2B1, STS, an enzyme of sterol desulfonation, protected against choroidal neovascularization development by activating LXR-ABCA1/G1 signalling to block M2 polarization. Collectively, these data reveal a cholesterol metabolism axis related to macrophage polarization in neovascular AMD.
© 2023 Wang et al.

Base editing technology is an ideal solution for treating pathogenic single-nucleotide variations (SNVs). No gene editing therapy has yet been approved for eye diseases, such as retinitis pigmentosa (RP). Here, we show, in the rd10 mouse model, which carries an SNV identified as an RP-causing mutation in human patients, that subretinal delivery of an optimized dual adeno-associated virus system containing the adenine base editor corrects the pathogenic SNV in the neuroretina with up to 49% efficiency. Light microscopy showed that a thick and robust outer nuclear layer (photoreceptors) was preserved in the treated area compared with the thin, degenerated outer nuclear layer without treatment. Substantial electroretinogram signals were detected in treated rd10 eyes, whereas control treated eyes showed minimal signals. The water maze experiment showed that the treatment substantially improved vision-guided behavior. Together, we construct and validate a translational therapeutic solution for the treatment of RP in humans. Our findings might accelerate the development of base-editing based gene therapies.
© 2023. Springer Nature Limited.