Proceedings of the Nutrition Society

Symposium 5: Muscle hypertrophy: the signals of insulin, amino acids and exercise

Calcineurin and skeletal muscle growth

Robin N. Michela1 c1, Shannon E. Dunna1 and Eva R. China2

a1 Neuromuscular Research Laboratory, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada

a2 Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research & Development, Eastern Pt Rd, MS8220-3120, Groton, CT 06340, USA

Abstract

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 Ca2+-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.

Correspondence:

c1 *Corresponding author: Dr Robin N. Michel Fax: +1 705 673 6508, Email: RNMichel@nickel.laurentian.ca