ArticleJournal of cachexia, sarcopenia and muscle2025
The Novel MuRF2 Target SNX5 Regulates PKA Activity Through Stabilization of RI-α and Controls Myogenic Differentiation.
Article in Journal of cachexia, sarcopenia and muscle, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
1 citing paper in PubMed.
- The Novel MuRF2 Target SNX5 Regulates PKA Activity Through Stabilization of RI-α and Controls Myogenic Differentiation.Journal of cachexia, sarcopenia and muscle · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors.
Funding
Abstract
backgroundMuscle RING finger (MuRF) proteins are striated muscle-specific E3 ubiquitin ligases essential for muscle homeostasis. Whereas MuRF1 is well known for its role in muscle atrophy, MuRF2 and MuRF3 contribute to microtubule stabilization, influencing muscle differentiation and function. Their cooperative functions in regulating myogenesis are unclear. This study aimed to identify novel MuRF2 and MuRF3 interaction partners and investigate their function in myogenic differentiation.
methodsInteraction partners of MuRF2 and MuRF3 were identified using stable isotope labelling with amino acids in cell culture (SILAC), followed by affinity purification and quantitative mass spectrometry (AP-MS). Mechanistic analyses included co-immunoprecipitation, domain mapping, ubiquitination assays, protein stability measurements and endosome isolation. Myogenic differentiation was evaluated by immunocytochemistry, qRT-PCR and western blotting. Functional effects were assessed using CRISPR-Cas9-mediated knockout and siRNA silencing.
resultsWe identified sorting nexin 5 (SNX5), a BAR and PX domain-containing retromer component involved in retrograde vesicular transport, as a novel MuRF2 and MuRF3 binding partner. Both coiled-coil domains of MuRF3 were required for SNX5 binding, and the BAR domain of SNX5 mediated interaction with MuRF2 and MuRF3. Immunofluorescence staining demonstrated MuRF3-SNX5 interaction and colocalization on early endosomes along microtubules in myocytes. MuRF2 promoted ubiquitination of SNX5 at lysines 290 and 324, leading to proteasomal degradation, whereas MuRF3 counteracted this effect. Mass spectrometry revealed the protein kinase A regulatory subunit (PKA-RI-α) as cargo of SNX5-coated early endosomes in myocytes. SNX5 knockout (SNX5-KO) reduced RI-α stability in myocytes, enhanced PKA activity and increased HDAC5 degradation via the autophagy-lysosomal pathway, leading to MEF2-mediated upregulation of myostatin. SNX5-KO impaired myogenesis, with significant reductions in myogenin/Myog (p < 0.005), myomaker/Mymk (p < 0.01), myomerger/Mymx (p < 0.005) and MyHC isoforms Myh2 and Myh4 (p < 0.01). Myostatin treatment mimicked the SNX5-KO phenotype, reducing fast-twitch MyHC isoforms Myh1, Myh2, Myh3 and Myh4 (p < 0.05 for all) and significantly lowering Myomaker, Myomerger and MyHC expression throughout differentiation (p < 0.05 for all). Morphologically, myostatin-treated cells were shorter and thinner and had fewer nuclei. Quantification showed reduced differentiation and fusion indices (p < 0.001) and fewer nuclei per myosin-positive cell (p < 0.01).
conclusionsMuRF2 and MuRF3 exert opposing effects on SNX5-mediated retrograde transport, influencing PKA signalling and myogenic differentiation. SNX5 stabilizes RI-α within early endosomes, facilitating ordered myogenic differentiation. Our findings expand the known functions of MuRF proteins beyond proteasomal degradation and identify SNX5 as a key regulator of PKA activity in muscle cells. These insights may provide novel therapeutic targets for muscle-related disorders.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.