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.
G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy
White, James P. , Wrann, Christiane D. , Rao, Rajesh R., Nair, Sreekumaran K., Jedrychowski, Mark P., You, Jae‐Sung , Martínez-Redondo, Vicente, Gygi, Steven P. , Ruas, Jorge L. , Hornberger, Troy A. , Wu, Zhidan , Glass, David J. , Piao, Xianhua , Spiegelman, Bruce M. , Nair, Sreekumaran K.
Proceedings of the National Academy of Sciences | October 22, 2014 | Volume: 111 | Issue: 44 | Pages: 15756-15761
Significance The work reported in this paper describes a previously unknown signaling pathway in skeletal muscle acting through G protein-coupled receptor 56-Galpha12/13. This discovery elucidates a previously unknown mechanism of muscle anabolism and gives another target of investigation for therapies against the loss of muscle mass seen with aging and various wasting diseases.