Lucas Lathan, Nitschke Larissa, Nguyen Brandon, Loehr James A, Rodney George G, Cooper Thomas A
Chemical, Physical, Structural Biology Graduate Program, Baylor College of Medicine, Houston, TX, USA.
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
iScience. 2024 Oct 5;27(11):111104. doi: 10.1016/j.isci.2024.111104. eCollection 2024 Nov 15.
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.
骨骼肌细胞（肌纤维）是细长的、无有丝分裂能力的多核细胞合体，其具有适应的微管晶格。微管相关蛋白（MAPs）在调节微管结构中发挥作用。骨骼肌中最丰富的MAP是MAP4。MAP4由一种在大多数组织中表达的普遍存在的MAP4亚型（uMAP4）和一种横纹肌特异性可变剪接亚型（mMAP4）组成，mMAP4包含一个3180个核苷酸的外显子（外显子8）。为了确定mMAP4在骨骼肌中的作用，我们构建了由于外显子8的基因组缺失而缺乏mMAP4且仅表达uMAP4的小鼠。我们证明，mMAP4的缺失导致微管结构紊乱和力产生的内在丧失。我们表明，与uMAP4相比，mMAP4与微管的结合增强，并且mMAP4的缺失和uMAP4的同时增加都会导致肌肉功能丧失。这些结果证明了mMAP4和uMAP4的平衡表达对骨骼肌稳态的关键作用。
