Myostatin (for muscle growth) theraputics update

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Abstract from Proc Nutr Soc. 2004 May;63(2):341-9.

Calcineurin and skeletal muscle growth.

Michel RN, Dunn SE, Chin ER.

Neuromuscular Research Laboratory, Department of Chemistry and

Biochemistry, tian University, Sudbury, Ontario P3E 2C6, Canada.

Recruitment determines the profile of fibre-type-specific genes

expressed across the range of muscle fibres associated with slow, fast

fatigue-resistant and fast fatiguable motor units. Downstream signalling

pathways activated by neural signalling and mechanical load have been

the focus of intensive research in past years. It is now known that

Ca(2+)-dependent calcineurin-nuclear factor of activated T cells and

insulin-like growth factor 1 pathways and their downstream mediators

contribute to these adaptive responses. These pathways regulate gene

expression through muscle-specific (myocyte-enhancing factor 2, myoblast

determination protein) and non-specific (nuclear factor of activated T

cell 2, GATA-2) transcription factors. Transcriptional signals activated

with increased contractile activity result in altered expression of

fibre-type specific genes, including the myosin heavy chain isoforms and

oxidative and glycolytic enzymes and a net change in muscle fibre-type

composition. In contrast, transcriptional signals activated by increased

load bearing result in hypertrophy or a growth response, a component of

which involves satellite cell recruitment and fusion with existing adult

myofibres. Calcineurin has been identified as a key mediator in the

hypertrophic response, and the current challenge has been to determine

the downstream target genes of this pathway. Exciting new data have

emerged, showing that myostatin, a negative regulator of muscle growth,

and utrophin, a cytoskeletal protein important in maintaining membrane

integrity, are downstream targets of calcineurin signalling. Increased

understanding of these mediators of muscle growth may provide strategies

for the development of effective therapeutics to counter muscle weakness

and muscular dystrophy.