Abstract
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.
Highlights
Throughout skeletal muscle development, myonuclei actively move to settle at specific locations in the fully differentiated muscle fibers where they are regularly spaced along the longitudinal fiber axis, sitting at the periphery underneath the surface membrane (Roman andGomes, 2017)
To determine whether MACF1 is important for skeletal muscle development, we addressed its role during myotubes formation and in mature myofibers
As we identified that microtubule network is altered along muscle fibers in MACF1-depleted condition, we analyzed the potential changes in tyrosinated/de-tyrosinated tubulin distribution at the neuromuscular junction (NMJ)
Summary
Throughout skeletal muscle development, myonuclei actively move to settle at specific locations in the fully differentiated muscle fibers (myofibers) where they are regularly spaced along the longitudinal fiber axis, sitting at the periphery underneath the surface membrane (Roman andGomes, 2017). Failure in proper extra-synaptic myonuclei patterning has been linked to different myopathies and muscle weakness (Collins et al, 2017; Falcone et al, 2014; Metzger et al, 2012; Perillo and Folker, 2018; Roman et al, 2017). This precise organization is correlated with a particular “flatten” shape of the myonuclei, whose alteration has recently emerged as a potential contributor to several muscular diseases How myonuclei positioning in mature myofibers is set and how it regulates the signaling pathways maintaining myofiber integrity is still poorly understood
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