Abstract
Myocyte Stress Protein 1 (MS1) is a muscle-specific, stress-responsive, regulator of gene expression. It was originally identified in embryonic mouse heart which showed increased expression in a rat model of left ventricular hypertrophy. To determine if MS1 was responsive to other stresses relevant to cardiac myocyte function, we tested if it could be induced by the metabolic stresses associated with ischaemia/reperfusion injury in cardiac myocytes. We found that metabolic stress increased MS1 expression, both at the mRNA and protein level, concurrent with activation of the c-Jun N-terminal Kinase (JNK) signalling pathway. MS1 induction by metabolic stress was blocked by both the transcription inhibitor actinomycin D and a JNK inhibitor, suggesting that activation of the JNK pathway during metabolic stress in cardiac myocytes leads to transcriptional induction of MS1. MS1 was also found to be an efficient JNK substrate in vitro, with a major JNK phosphorylation site identified at Thr-62. In addition, MS1 was found to co-precipitate with JNK, and inspection of the amino acid sequence upstream of the phosphorylation site, at Thr-62, revealed a putative Mitogen-Activated Protein Kinase (MAPK) binding site. Taken together, these data identify MS1 as a likely transcriptional and post-translational target for the JNK pathway in cardiac myocytes subjected to metabolic stress.
Highlights
Myocyte stress protein 1 (MS1) is a myofibrillar protein involved in the regulation of gene expression in both cardiac and skeletal muscle
Induction of MS1 mRNA during recovery from metabolic stress in cardiac myocytes To determine if the cellular stresses associated with ischaemiareperfusion injury affected the level of MS1 expression in cardiac myocytes, MS1 mRNA levels in both neonatal cardiac myocytes and H9c2 cardiac myoblasts were determined by northern blotting and RT-polymerase chain reaction (PCR) (Fig. 1A & 1B) following treatment with metabolic inhibitors and recovery
The recent literature on MS1 [5, 6, 10, 27, 40, 41, 42] and our previous work on stress-activated signalling pathways in cardiac myocytes [22, 33, 34] suggested that MS1 might be induced by metabolic stress in cardiac myocytes and that there may be a link between the Jun N-terminal Kinase (JNK) signalling pathway and MS1
Summary
Myocyte stress protein 1 (MS1) is a myofibrillar protein involved in the regulation of gene expression in both cardiac and skeletal muscle. It is known as striated muscle activator of Rho Signalling and Serum Response Factor dependent transcription (STARS)[1] or Actin-binding Rhoactivating protein (ABRA)[2]. More recent evidence suggests that MS1 likely plays a key role in regulating many aspects of myocyte cell physiology during development, in regeneration after injury and in the adaptive responses to metabolic and mechanical stresses experienced by both cardiac and skeletal muscle [5, 6, 7]. G-actin thereby dissociates from the Myocardin Related Transcription Factor-A (MRTF-A), allowing it to translocate to the nucleus, where, in collaboration with Serum Response Factor (SRF) acting at the Serum Response Element (SRE), it switches on the hypertrophic gene programme involved in muscle cell proliferation, growth and repair [1, 4, 9, 10]
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