265
supporting their conclusion of reduced fibrogenesis included decreased expression
of tissue inhibitor of metalloproteinase-1 (TIMP-1) with unchanged expression of
matrix metalloproteinase-1 (MMP-1) as well as reduction of the collagen volume
fraction in the exercised animals [ 42 ].
One of the most significant advancements in the study of gene expression regula-tion has been the recent elucidation of the important roles of miRNAs. A compila-
tion of studies has concluded that a single miRNA can target hundreds of different
mRNA species, each with a varying degree of efficacy. Since an individual mRNA
can be affected by many different miRNAs, one can only imagine the very elaborate
and complex nature of the regulatory control systems that miRNA could impose on
gene expression programs. A number of miRNAs have also been shown to modulate
intracellular events such as hypertrophy, muscle recovery, the metabolism of mito-
chondria as well as inflammatory processes. They are therefore an interesting and
relevant way of evaluating the body’s response to physical exercise. The character-
ization of patterns of miRNA expression that are most associated with the effects of
exercise and training could prove useful in the estimation of physical performance
capacity and the tracking of muscle fatigue and recovery [ 52 ]. Two miRNAs, miR-1
and miR-133, were found to be decreased in two models of physiological cardiac
hypertrophy. One model used transgenic mice with the selective cardiac overexpres-
sion of a constitutively-active Akt kinase and the other model displayed cardiac
hypertrophy that was induced in exercised trained rats [ 48 , 49 ]. In rats undergoing a
training program of aerobic swimming, the expression of miR-29c was increased.
Furthermore, downregulation of miR-29 increased the accumulation of collagen
and worsened fibrosis in the heart whereas the overexpression of miR-29 resulted in
the opposite effects [ 50 , 51 ]. Some newly described microRNA molecules such as
miR-17-3p might serve as a novel therapy in association with exercise for enhanc-
ing cardiac survival and regeneration [ 53 ].
5 Conclusion
Fibroblasts are essential and dynamic cells in the mammalian heart. They are cru-
cial to cardiac development and to the response to injury. Fibroblasts establish and
maintain the mechanical, biochemical, and electrical environment of the heart
through their intricate interactions with cardiomyocytes. Cardiac injury disrupts the
balance between fibroblasts and cardiomyocytes and creates a state favouring
inflammation and fibrosis. This adaptive response initially serves to increase wound
healing. If homeostasis is not regained, however, the heart may be damaged and
heart failure may ensue.
Myofibroblasts are mediators of both the adaptive and maladaptive componentsof this reaction. By furthering our understanding of the beneficial and deleterious
roles of cardiac fibroblasts and myofibroblasts and how these roles are related to
each other in cardiac development and in heart disease, we may be able to design
interventions to prevent the progression of cardiac fibrosis.
14 Cardiac Fibrosis: The Beneficial Effects of Exercise in Cardiac Fibrosis