MACF1 controls skeletal muscle function through the microtubule-dependent localization of extra-synaptic myonuclei and mitochondria biogenesis

eLife

Lilia Laddada¹  Christophe Jagla¹  Cedric Soler¹  Valerie Risson²  Francisco-Ignacio Jaque-Fernandez²  Emilie Christin²  Alireza Ghasemizadeh²  Colline Sanchez²  Vincent Jacquemond²  Laurent Schaeffer²  Julien Gondin²  Marine Lanfranchi²  Alexandre Guiraud²  Julien Courchet²  Nathalie Couturier²  Vincent Gache²  Emmanuelle Girard²  Jean-Luc Thomas²  Marie Abitbol³ 

[1] GReD Laboratory, Clermont-Auvergne University, INSERM U1103, CNRS, Clermont-Ferrand, France;Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon I, Lyon Cedex, France;Institut NeuroMyoGène, CNRS UMR5310, INSERM U1217, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon I, Lyon Cedex, France;Université Marcy l’Etoile, VetAgro Sup, Lyon, France;

关键词: microtubules;    nucleus;    muscle fiber;    mitochondria;    neuromuscular junction;    cytoskeleton;    D. melanogaster;    Mouse;   

DOI  :  10.7554/eLife.70490

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Skeletal muscles are composed of hundreds of multinucleated muscle fibers (myofibers) whose myonuclei are regularly positioned all along the myofiber’s periphery except the few ones clustered underneath the neuromuscular junction (NMJ) at the synaptic zone. This precise myonuclei organization is altered in different types of muscle disease, including centronuclear myopathies (CNMs). However, the molecular machinery regulating myonuclei position and organization in mature myofibers remains largely unknown. Conversely, it is also unclear how peripheral myonuclei positioning is lost in the related muscle diseases. Here, we describe the microtubule-associated protein, MACF1, as an essential and evolutionary conserved regulator of myonuclei positioning and maintenance, in cultured mammalian myotubes, in Drosophila muscle, and in adult mammalian muscle using a conditional muscle-specific knockout mouse model. In vitro, we show that MACF1 controls microtubules dynamics and contributes to microtubule stabilization during myofiber’s maturation. In addition, we demonstrate that MACF1 regulates the microtubules density specifically around myonuclei, and, as a consequence, governs myonuclei motion. Our in vivo studies show that MACF1 deficiency is associated with alteration of extra-synaptic myonuclei positioning and microtubules network organization, both preceding NMJ fragmentation. Accordingly, MACF1 deficiency results in reduced muscle excitability and disorganized triads, leaving voltage-activated sarcoplasmic reticulum Ca2+ release and maximal muscle force unchanged. Finally, adult MACF1-KO mice present an improved resistance to fatigue correlated with a strong increase in mitochondria biogenesis.

【 授权许可】

CC BY