Citations 2
The E3 ligase HECTD1 controls skeletal muscle sarcomere and mitochondrial integrity
Ruas, Jorge L. , Červenka, Igor , Leuchtmann, Aurel B. , Jannig, Paulo R. , Naddaf, Elie, Kokesh, Elieen, Murgia, Marta , Sereiva, Tadas , Li, Bo , Yang, Feikun , Jude, Baptiste , Rumyantseva, Anastasia , Azzolini, Michelle, Porsmyr‐Palmertz, Margareta, Yang, Wenli , Mann, Matthias, Töpf, Ana , Straub, Volker, Naddaf, Elie , Naddaf, Elie , Ducommun, Serge , Correia, Jorge C. , Mann, Matthias , Freyer, Christoph , Wredenberg, Anna , Lanner, Johanna T. , Hahn, A. , Straub, Volker
No container title available | March 8, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Sarcomeres are the fundamental functional units of skeletal muscle, essential for both force generation and metabolic homeostasis. While sarcomere degradation has been extensively studied, the mechanisms that preserve its integrity remain poorly defined. Here, we identify HECTD1 as an E3 ubiquitin ligase required for sarcomere maintenance and mitochondrial integrity. We show that HECTD1 ubiquitylates and stabilizes the chaperones KLHL40/41, which protect thin-filament components from misfolding and degradation. Consequently, reducing Hectd1 expression in myotubes coordinately decreases the levels of multiple sarcomere proteins. Skeletal muscle–specific Hectd1 knockout mice ( Hectd1 mKO) show severe sarcomere and mitochondrial disorganization and dysfunction, progressive muscle weakness, exercise and glucose intolerance, and unresolved tissue remodeling. Importantly, human iPSC-derived myotubes carrying a patient-associated HECTD1 mutation, recapitulate key molecular features of the Hectd1 mKO. These findings establish HECTD1 as a central regulator linking sarcomere proteostasis to mitochondrial function and identify its dysfunction as a cause of myopathy with mitochondriopathy.
A randomized, double-blind, placebo-controlled study of losmapimod in patients with facioscapulohumeral muscular dystrophy: Results of the REACH study
Voermans, Nicol C, Statland, J., Hayward, Lawrence J. , Rosenbohm, Angela , Munain, Adolfo López de, Sacconi, Sabrina, Leung, D., Vissing, John, Schoser, Benedikt, Lochmüller, H., Bugiardini, E., Wang, Leo H. , Maggi, Lorenzo, Ragole, Thomas , Pestronk, Alan , Hamel, Johanna , Goyal, Namita A, Korngut, Lawrence, Naddaf, Elie, Harper, A., Shieh, Perry, Kornblum, Cornelia , Sansone, Valeria, Genge, A., Tasca, G., Jiang, John , Jouvin, Marie‐Hélène , Tawil, Rabi , Investigators, on behalf of the REACH, Leung, Doris G , Muelas, Nuria , Wang, Leo H , Pestronk, Alan , Goyal, Namita A , Harper, Amy , Tasca, Giorgio , Tawil, Rabi , Voermans, Nicol Cornelia , Statland, Jeffrey M., Munaín, Adolfo López de , Sacconi, Sabrina , Badrising, Umesh A. , Vissing, John , Schoser, Benedikt , Bugiardini, Enrico , Maggi, Lorenzo , Korngut, Lawrence , Naddaf, Elie , Shieh, Perry B. , Sansone, Valeria , Genge, Angela
Journal of Neuromuscular Diseases | February 6, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Background: Losmapimod is an orally administered small molecule and selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor able to reduce aberrant expression of DUX4 in vitro and thereby potentially slowing disease progression in patients with facioscapulohumeral muscular dystrophy (FSHD). Objective: This global, randomized, placebo-controlled, double-blind phase 3 study in patients with FSHD1 and FSHD2 examined the efficacy and safety of losmapimod over a 48-week treatment period compared to placebo (NCT05397470, EUDRACT 2022-000389-16). Methods: The primary endpoint was change in quantification of reachable workspace (RWS) expressed as relative surface area (RSA). Other endpoints included measures of muscle composition (fat content and lean muscle) using magnetic resonance imaging (MRI), muscle strength using quantitative dynamometry, and quality of life measures. Results: 130 participants received losmapimod and 130 participants received placebo, with 252 participants completing the 48-week treatment period. There were no statistically significant differences between groups in change in RSA and all secondary efficacy endpoints from baseline to Week 48. Losmapimod treatment was well-tolerated, and most adverse events were mild. Conclusions: Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies.