Regulation of mechano growth factor in skeletal muscle and heart

Abstract

The mechano growth factor (MGF) is expressed in mechanically overloaded skeletal muscle. MGF was discovered in 1996 as an alternative splice product of the IGF-1 gene. Since then, its significance has been investigated particularly in skeletal muscle, because the local expression of MGF could provide an explanation for the specific hypertrophy of overloaded muscle. In the present thesis, regulation of MGF in skeletal muscle and heart was investigated, and compared with that of IGF-1Ea. The first experimental Chapter shows that a single bout of 15 min of lengthening contractions initiates a number of various molecular responses in isolated mouse skeletal muscle, independent of any circulating systemic factor. Simultaneously with contraction-induced MGF mRNA expression, genes like MyoD and PCNA were induced suggesting the activation muscle stem cells. The subsequently observed mRNA expression of IGF-1Ea might stimulate differentiation of muscle stem cells into myotubes. At that time PCNA mRNA is no longer expressed is, indicating stem cells are no longer in the S-phase. Because MGF was induced in skeletal muscle by mechanical loading, its expression in heart was investigated in a series of in vivo and in vitro experiments. In mice treated with thyroid hormone (T3) for 12 days to induce cardiac hypertrophy, cardiac MGF expression strongly correlated with the increased beating frequency in hyperthyroid mice. In contrast to skeletal muscle, MGF was constitutively expressed in the heart, may be as a result of its continuous activity. The in vivo observations were compared to heart cells exposed to T3 in culture. Upon T3 treatment, cardiomyocytes showed an increase in beats per minute, as well as increases in MGF and IGF-1Ea mRNA expression. Interestingly, when the T3-exposed cardiomyocytes were contractile arrested by KCl, up-regulation of MGF was not observed, whereas IGF-1Ea was still induced. These findings suggest that MGF is induced in mechanically stressed cardiomyocytes and potentially mediates the adaptive hypertrophic response towards thyroid hormone treatment. The next Chapter shows that expression of MGF increases during early cardiac embryonic development, decreases during postnatal development, and re-emerges shortly after acute myocardial infarction in adult mice. Since myocardial infarction results in an insufficient supply of oxygen and nutrition into the infarcted area, we evaluated the influence of hypoxia and starvation on MGF expression. We exposed cardiomyocyte cell cultures to desferrioxamine (DFO), which stabilizes hypoxia-inducible factor-1α (HIF-1α), and found induction of MGF. In contrast, starvation of cardiomyocytes decreased MGF. These findings demonstrate that MGF is induced during embryonic development and upon ischemic injury of the heart, where hypoxia/HIF-activated pathways are likely to be important for MGF regulation, rather than nutritional shortage. In conclusion, the results presented in this thesis contribute to the understanding of the regulation of the Mechano Growth Factor. The final Chapter focuses on the possible beneficial effects of MGF on health. It addresses the issue whether MGF could be useful for a therapeutic approach in patients with muscle or heart diseases, as well as the (mis)use of MGF in sports.