Marked reduction of focal adhesion kinase, serum response factor and myocyte enhancer factor 2C, but increase in RhoA and myostatin in the hindlimb dy mouse muscles.

Abstract

Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration. This is probably due to decreased formation of multi nucleated myotubes resulting from a myoblast fusion defect. When receiving a mechanical signal from muscle membranes, a cascade of RhoA, focal adhesion kinase (FAK), and serum response factor (SRF) positively regulates myogenesis and muscle hypertrophy associated with functional overload. In contrast, myostatin, a potent negative regulator of skeletal muscle hypertrophy, appears to be up-regulated in the muscles of mdx mice, an animal model for Duchenne muscular dystrophy. Using Western blot and immunohistochemical analyses, we investigated the levels of RhoA, FAK, SRF, and myostatin in the skeletal muscles of dy mice. The amount of RhoA protein was increased in the hindlimb muscles of dy mice aged 12 weeks. At 12 weeks, FAK immunoreactivity was observed in the myonuclei and/or satellite cells of normal mice, but not of dy mice. SRF protein levels decreased markedly in the gastrocnemius and rectus femoris muscles of dy mice at 2 and 12 weeks. Several muscle fibers in normal mice possessed uniform SRF immunoreactivity in the cytoplasm. An SRF immunostaining pattern in muscle was not detected in dy mice. Western blot and the densitometric analysis showed a decreased amount of myocyte enhancer factor 2C (MEF2C) in hindlimb muscles of dy mice. Although slight myostatin immunoreactivity was observed in the nuclei of some normal mice, marked myostatin immunoreactivity was observed in the cytoplasm of mature dy mice myonuclei and/or satellite cells. A low expression of FAK, SRF and MEF2C in muscles of dy mice may inhibit postnatal muscle hypertrophy by fusing satellite cells with existing fibers. Enhancing myostatin protein would result in further atrophy and degeneration of muscle fiber in dy mice.

• Authors: Kunihiro Sakuma, Ryuta Nakao, Shuichiro Inashima, Miyuki Hirata, Toshikazu Kubo, Masahiro Yasuhara
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 108 Issue 3 Pg. 241-9 (Sep 2004) ISSN: 0001-6322 [Print] Germany
• PMID: 15221330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin beta Chains
• MEF2 Transcription Factors
• Mef2c protein, mouse
• Mstn protein, mouse
• Myogenic Regulatory Factors
• Myostatin
• Serum Response Factor
• Transforming Growth Factor beta
• Protein-Tyrosine Kinases
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• Ptk2 protein, mouse
• rhoA GTP-Binding Protein

Topics

• Animals
• Blotting, Western
• Disease Models, Animal
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• Hindlimb (physiology)
• Immunohistochemistry
• Integrin beta Chains
• MEF2 Transcription Factors
• Mice
• Muscle, Skeletal (chemistry, metabolism, pathology)
• Muscular Dystrophy, Animal (metabolism)
• Myogenic Regulatory Factors (metabolism)
• Myostatin
• Protein-Tyrosine Kinases (metabolism)
• Serum Response Factor (metabolism)
• Signal Transduction (physiology)
• Transforming Growth Factor beta (metabolism)
• rhoA GTP-Binding Protein (metabolism)