Αnastassios Philippou

Muscle injury induces strong changes in muscle cells and extracellular matrix. Muscle regeneration after injury has similarities to muscle development during embryogenesis and seems to follow the same procedure. The initial phase of muscle repair is characterized by inflammation and degeneration of the damaged tissue. Almost simultaneously, previous quiescent myogenic cells, called satellite cells, are activated, proliferate, differentiate and fuse to form multinucleated myofibers. Other non-muscle stem cells may also take part in this process. Secreted factors, such as hepatocyte growth factor (HGF), fibroblast growth factors (FGFs), transforming growth factor-betas (TGF-betas), insulin-like growth factors (IGFs), tumour necrosis factor alpha (TNFalpha) and others, are released during muscle repair and guide muscle regeneration, however, their exact functions and effects on muscle remodeling remain unknown. Intensive research is currently addressing the regenerative mechanisms which are involved in acute muscle injuries and chronic muscle diseases.

Mitochondria are the source of cellular energy production and are present in different types of cells. However, their function is especially important for the heart due to the high demands in energy which is achieved through oxidative phosphorylation. Mitochondria form large networks which regulate metabolism and the optimal function is achieved through the balance between mitochondrial fusion and mitochondrial fission. Moreover, mitochondrial function is upon quality control via the process of mitophagy which removes the damaged organelles. Mitochondrial dysfunction is associated with the development of numerous cardiac diseases such as atherosclerosis, ischemia-reperfusion (I/R) injury, hypertension, diabetes, cardiac hypertrophy and heart failure (HF), due to the uncontrolled production of reactive oxygen species (ROS). Therefore, early control of mitochondrial dysfunction is a crucial step in the therapy of cardiac diseases. A number of anti-oxidant molecules and medications have been used but the results are inconsistent among the studies. Eventually, the aim of future research is to design molecules which selectively target mitochondrial dysfunction and restore the capacity of cellular anti-oxidant enzymes.

Skeletal muscle is able not only to increase its mass as an adaptation to mechanical loading generated by and imposed upon muscle but also to regenerate after damage, via its intrinsic regulation of gene transcription. Both cellular processes, muscle regeneration and hypertrophy, are mediated by the activation, proliferation and differentiation of muscle satellite cells and appear to be modulated by the mitotic and myogenic activity of locally produced insulin-like growth factor 1 (IGF-1), which functions in an autocrine/paracrine mode. Differentiation of satellite cells into myoblasts involves the regulation of skeletal muscle-specific proteins belonging to the family of myogenic regulatory factors (MRFs). The endocrine, autocrine and paracrine functions of IGF-1 are mediated through binding to the type I IGF receptor (IGF-1.R), which is a ligand-activated receptor tyrosine kinase. The binding of IGF-1 to IGF-1.R induces its autophosphorylation, which recruits specific cytoplasmic molecules containing the Insulin Receptor Substrate Proteins (IRS). The recruitment of IRS proteins by IGF-1/IGF-1.R binding is a critical level at which the proliferative and differentiative actions of IGF-1 diverge. Specific signaling pathways downstream of IGF-1, potentially involved in the mitogenic and myogenic responses and mediating skeletal muscle protein synthesis and hypertrophy following exercise-induced muscle overloading and damage, are discussed. A potential alternative activation of different signaling pathway(s) via a different receptor remains to be demonstrated.