Skeletal muscle MACF1 maintains myonuclei and mitochondria localization through microtubules to control muscle functionalities

Abstract

Skeletal muscle is made from multinuclear myofiber, where myonuclei are positioned at the periphery or clustered below neuromuscular junctions (NMJs). While mispositioned myonuclei are the hallmark of numerous muscular diseases, the molecular machinery maintaining myonuclei positioning in mature muscle is still unknown. Here, we identified microtubule-associated protein MACF1 as an evolutionary conserved regulator of myonuclei positioning, in vitro and in vivo, controlling the “microtubule code” and stabilizing the microtubule dynamics during myofibers maturation, preferentially at NMJs. Specifically, MACF1 governs myonuclei motion, mitochondria positioning and structure and acetylcholine receptors (AChRs) clustering. Macf1-KO in young and adult mice decreases muscle excitability and causes evolutionary myonuclei positioning alterations in adult mice, paralleled with high mitochondria content and improved resistance to fatigue. We present MACF1 as a primary actor of the maintenance of synaptic myonuclei and AChRs clustering, peripheral myonuclei positioning and mitochondria organization through the control of microtubule network dynamics in muscle fibers.

Genome-Wide Atlas of Promoter Expression Reveals Contribution of Transcribed Regulatory Elements to Genetic Control of Disuse-Mediated Atrophy of Skeletal Muscle

“…Similarly, 28 genes were both upregulated and changed their dominating TSSs in fast muscle on the first day of recovery, including Ampd3, a subunit of AMP deaminase [ 25 ], Ankh, a mediator of cellular export of ATP; Dapk2, which is phosphorylated in a Ca 2+ -independent manner by AMPK in muscle tissue, undergoing dystrophy [ 26 ]; Flt1, a VEGF receptor, essential for skeletal muscle function [ 27 ]; Lpin1, which is essential for lipid metabolism and ATP synthesis [ 28 ]; Macf1, which maintains cellular components of microtubules in muscle [ 29 ]; Myl12a, myosin regulatory subunit; Prkag2, whose mutations are associated with skeletal muscle glycogenosis [ 30 ]; Xirp1, a marker of wounded skeletal muscle [ 31 ].…”

SH3KBP1 scaffolds endoplasmic reticulum and controls skeletal myofibers architecture and integrity

“…A few proteins have been shown to form a flexible perinuclear shield that can protect myonuclei from extrinsic forces (Wang et al, 2015;Ghasemizadeh et al, 2019). To note, recent data show that disruption of one component of this perinuclear shield, MACF1 protein, increases myonuclei velocity (Ghasemizadeh et al, 2019). Consequently, SH3KBP1 probably belongs to the group of proteins that contribute to the stability of this perinuclear shield through the maintenance of ER at the vicinity of myonuclei.…”

“…Interestingly, in CNM-KI-Dnm2 R465W mouse model, Fongy et al show that myonuclei move and spread properly in heterozygous myotubes but hypothesize a defect in nuclear anchoring at the periphery (Fongy et al, 2019). Several studies pointed the importance of cytoskeleton, including MAPs, microtubules and intermediate filaments, in the nuclear anchorage in mature muscle (Ghasemizadeh et al, 2019;Roman et al, 2017). SH3KBP1 dependent ER-scaffolding could participate in myonuclei anchoring at the periphery of myofibers and thus in the recruitment and stabilization of a network of proteins at the vicinity of (which was not certified by peer review) is the author/funder.…”

Centrosome and ciliary abnormalities in fetal akinesia deformation sequence human fibroblasts

“…Signaling downstream of MuSK is only poorly understood, but it involves interactions of both MuSK and rapsyn to all three cytoskeleton networks, i.e. microtubules, the actin cytoskeleton and intermediate filaments (Aittaleb et al, 2015;Antolik et al, 2007;Bartoli et al, 2001;Dobbins et al, 2008;Ghasemizadeh et al, 2019;Li et al, 2016;Luiskandl et al, 2013;Mihailovska et al, 2014;Moransard et al, 2003;Oury et al, 2019). Rapsyn has, moreover, been found in non-muscle cell types Musil et al, 1989) and plays a role in lysosome clustering (Aittaleb et al, 2015).…”