Myosin VI Localization and Expression in Striated Muscle Pathology

Abstract

Myosin VI (MVI) is a unique unconventional myosin translocating, unlike other myosins, towards the minus end of actin filaments. It is involved in numerous cellular processes such as endocytosis, intracellular trafficking, cell migration, and transcription. In mammalian skeletal muscles it localizes mainly to sarcoplasmic reticulum and is also present within the muscle nuclei and at the neuromuscular junction (Karolczak et al. Histochem Cell Biol 2013; 23:219-228). We have also shown that in denervated rat hindlimb muscle the MVI expression level is significantly increased and its localization is changed, indicating an important role of MVI in striated muscle pathology. Here, we addressed this problem by examining the distribution and expression levels of myosin VI in biopsies of skeletal muscles from patients with different myopathies. We found that, particularly in myopathies associated with fiber atrophy, the amount of MVI was enhanced and its localization in affected fibers was changed. Also, since a mutation within the human MVI gene was shown to be associated with cardiomyopathy, we assessed MVI localization and expression level in cardiac muscle using wild type and MLP(2/2) mice, a dilated cardiomyopathy model. No significant difference in MVI expression level was observed for both types of animals. MVI was found at intercalated discs and also at the sarcoplasmic reticulum. In the knockout mice, it was also present in ring-like structures surrounding the nuclei. The data indicate that in striated muscle MVI could be engaged in sarcoplasmic reticulum maintenance and/or functioning, vesicular transport, signal transmission and possibly in gene transcription.

Involvement of unconventional myosin VI in myoblast function and myotube formation

“…Notably, its amount was significantly increased in atrophic fibers of muscle biopsies obtained from patients with several myopathies (Karolczak et al 2014). In humans, a point mutation (H246R) within the MVI gene was associated with cardiac hypertrophy, suggesting an important role of this molecular motor in striated muscles (Mohiddin et al 2004).…”

A Kinase Anchoring Protein 9 Is a Novel Myosin VI Binding Partner That Links Myosin VI with the PKA Pathway in Myogenic Cells

“…We have previously shown that MVI plays important roles both in skeletal and cardiac muscle [ 13 , 15 ] and in C2C12 myoblasts [ 14 ]. To further explore MVI function in myogenic cells, we performed a search for its binding partners by means of an affinity chromatography with the GST-tagged globular tail domain of MVI (GST-MVI-GT) used as a bait.…”

“…One of the mutations, a H246R mutation within the human MVI motor domain, was also found to be associated with hypertrophic cardiomyopathy [ 12 ] suggesting important role(s) of this motor in striated muscle. Indeed, our recent work has shown that in striated muscle as well as in myogenic cells MVI could be involved in the organization/maintenance of the sarcoplasmic reticulum, Golgi apparatus, adhesive structures (and intercalated discs in case of cardiac muscle), nuclei, and the neuromuscular junction [ 13 – 15 ]. We found that in skeletal muscles MVI might interact with TOM1 (target of myb1 homolog isoform 1, a protein involved in intracellular transport and autophagy), FMRP (fragile X mental retardation autosomal homolog 1, a protein involved in mRNA transport), and hnRNP proteins (involved in the RNA transport and maturation) [ 13 ].…”

Recent Advances in Muscle Research

“…There are about 20 classes of these molecules (Krendel and Mooseker, ; Hartman and Spudich, ). Redowicz and coworker (Karolczak et al, ) review the distribution and roles of one of these unconventional myosins, myosin VIA, in healthy and in diseased striated muscle cells.…”