Alternatively Spliced MAP4 Isoforms Have Key Roles in Maintaining Microtubule Organization and Skeletal Muscle Function

Authors

Lathan Lucas
Larissa Nitschke
Brandon Nguyen
James A Loehr
George G Rodney
Thomas A Cooper

Publication Date

11-15-2024

Journal

iScience

DOI

10.1016/j.isci.2024.111104

PMID

39473976

PMCID

PMC11513531

PubMedCentral® Posted Date

10-5-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Cellular physiology, Molecular physiology, Molecular Structure, Functional aspects of cell biology

Abstract

Skeletal muscle cells (myofibers) are elongated non-mitotic, multinucleated syncytia that have adapted a microtubule lattice. Microtubule-associated proteins (MAPs) play roles in regulating microtubule architecture. The most abundant MAP in skeletal muscle is MAP4. MAP4 consists of a ubiquitous MAP4 isoform (uMAP4), expressed in most tissues, and a striated-muscle-specific alternatively spliced isoform (mMAP4) that includes a 3,180-nucleotide exon (exon 8). To determine the role of mMAP4 in skeletal muscle, we generated mice that lack mMAP4 and express only uMAP4 due to genomic deletion of exon 8. We demonstrate that loss of mMAP4 leads to disorganized microtubule architecture and intrinsic loss of force generation. We show that mMAP4 exhibits enhanced association with microtubules compared to uMAP4 and that both the loss of mMAP4 and the concomitant gain of uMAP4 cause loss of muscle function. These results demonstrate the critical role for balanced expression of mMAP4 and uMAP4 for skeletal muscle homeostasis.