The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between
the mechanical stimulus and gene expression, represents a new and important area in the morphological
sciences. Several cell types (‘mechanocytes’), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and
skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this
involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of
mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be
accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to
changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and
immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown
that stretch is an important mechanical signal for the production of more actin and myosin filaments and
the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of
the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype.
Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which
encode different molecular motors is a means via which the tissue adapts to a given type of physical activity.
As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF that
is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and
remodelling. From its sequence it can be seen that it is derived from the IGF gene by alternative splicing
but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the
reading frame of the 3′ end. Therefore, this splice variant of IGF-1 is likely to bind to a different binding
protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be
expected to localise its action as it would be unstable in the unbound form which is important as its
production would not disturb the glucose homeostasis unduly. This new growth factor has been called
mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action.
Although the liver is usually thought of as the source of circulating IGF, it has recently been shown that
during exercise skeletal muscle not only produces much of the circulating IGF but active musculature also
utilises most of the IGF produced. We have cloned both an autocrine and endocrine IGF-1, both of
which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown
that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected
to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are
due to the lack of dystrophin (X-linked) and due to a laminin deficiency (autosomal), thus indicating that
the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this
complex is defective the necessary systemic as well as autocrine IGF-1 growth factors required for local
repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery
of the locally produced IGF-1 appears to provide the link between the mechanical stimulus and the
activation of gene expression.