The E3 ligase HECTD1 controls skeletal muscle sarcomere and mitochondrial integrity

Authors
Jorge Ruas, Igor Cervenka, Aurel Leuchtmann, Paulo Jannig, Serge Ducommun, Elie Naddaf, Elieen Kokesh, Jorge Correia, Marta Murgia, Tadas Sereiva, Bo Li, Feikun Yang, Baptiste Jude, Anastasia Rumyantseva, Michelle Azzolini, Margareta Porsmyr-Palmertz, Wenli Yang, Matthias Mann, Christoph Freyer, Anna Wredenberg, Johanna Lanner, Andreas Hahn, Ana Töpf, Volker Straub


Lab

Journal

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, reducingHectd1expression in myotubes coordinately decreases the levels of multiple sarcomere proteins. Skeletal muscle–specificHectd1knockout mice (Hectd1mKO) 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 theHectd1mKO. 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.

Keywords/Topics
both force generation; specifichectd1knockout mice; unresolved tissue remodeling; female hectd1 mko mice; basal grip strength; mice aged cohort; skeletal muscle sarcomere; mitochondrial integrity; sarcomeres; metabolic homeostasis

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.researchsquare.com/article/rs-8663318/latest

Produits associés

Test d'agrippement

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