Deletion of the microtubule-associated protein 6 (MAP6) results in skeletal muscle dysfunction
Abstract
Background : The skeletal muscle fiber has a specific and precise intracellular organization which is at the basis ofan efficient muscle contraction. Microtubules are long known to play a major role in the function and organizationof many cells, but in skeletal muscle, the contribution of the microtubule cytoskeleton to the efficiency ofcontraction has only recently been studied. The microtubule network is dynamic and is regulated by manymicrotubule-associated proteins (MAPs). In the present study, the role of the MAP6 protein in skeletal muscleorganization and function has been studied using the MAP6 knockout mouse line.
Methods : The presence of MAP6 transcripts and proteins was shown in mouse muscle homogenates and primary cultureusingRT-PCRandwesternblot.Theinvivoevaluationofmuscleforceof MAP6 knockout (KO) mice was performed on anesthetized animals using electrostimulation coupled to mechanical measurement and multimodal magnetic resonance. The impact of MAP6 deletion on microtubule organization and intracellular structures was studied using immunofluorescent labeling and electron microscopy, and on calcium release for muscle contraction using Fluo-4 calciumimaging on cultured myotubes. Statistical analysis was performed using Student’sttest or the Mann-Whitney test.
Results : We demonstrate the presence of MAP6 transcripts and proteins in skeletal muscle. Deletion of MAP6 results in alarge number of muscle modifications: muscle weakness associated with slight muscle atrophy, alterations of microtubulenetwork and sarcoplasmic reticulum organization, and reduction in calcium release.
Conclusion : Altogether, our results demonstrate that MAP6 is involved in skeletal muscle function. Its deletion results inalterations in skeletal muscle contraction which contributetotheglobaldeleteriousphenotypeoftheMAP6KOmice.AsMAP6 KO mouse line is a model for schizophrenia, our work points to a possible muscle weakness associated to someforms of schizophrenia.
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