**20. The necrosis of the muscular fibre**

**Fifth day**: the myoblasts collect inside the myotubes of the RZ and the connective tissue of the CZ starts to become

**Seventh day**: the repair processes of the muscular cells extend outside the old cylinders of the basal lamina up to the

**Fourteenth day:** the healing area in the CZ area is further condensed and reduced in dimension and the repaired

more dense.

30 Muscle Injuries in Sport Medicine

CZ area and start to penetrate through the scar area.

myo-fibres fill the remaining gap of the CZ area itself.

At the moment in which the skeletal muscle is injured, we can generally observe a mechanical force which extends through the whole transversal section of each single fiber and causes the breakage of the sarcolemma inside the stumps of already injured fibers; leaving the latter am‐ ply open. From the moment that the myofibrillars (and consequently the muscular fibers)are, from a structural point of view, cells of notable length and of a lengthened and tapered form, there exists a real risk that the process of necrosis, begun in the location of the injury, extends along the whole length of the fiber itself. However, there exists a special anatomic structure named "contraction band" made up of a particularly dense cytoskeletal material, which be‐ haves as a true "fire door" (Hurme et al., 1991). Some hours following the traumatic event, the propagation of the necrotic process is blocked by a local phenomena represented by a sort of seal carried out by the contraction band on a level of modified areas of the cellular membrane. In such a way, a sort of protective barrier is created inside which starts the repair processes re‐ garding the laceration of the cellular membrane (Hurme et al., 1991). Recent studies have also shown that the lysosomal vesicles found inside the site of destruction of the cellular membrane, cover the role of a temporary membrane and carry out a central task in the healing process of the cellular membrane (Miyake et al., 2001; McNeil, 2002).

## **21. The inflammatory phase**

Contextually into the muscular fiber injury, in the traumatic event, also the blood vessels of the injured muscle tissue are lacerated. In such a way the inflammatory cells, transported by the blood flow, have direct access to the injured site. The inflammatory reaction is "amplified" by the fact that the satellite cells and the necrotic parts of the injured muscular fibers, release several substances defined "wound hormones", which behave as chemo-attractant increasing in such a way the overflowing of the inflammatory cells (Tidball, 1995; Chazaud et al., 2003; Hirata et al., 2003;). Inside the injured muscle, we may observe macrophages and fibro-blasts whose activation gives origin to the additional chemo-tactic signals (as growth factor, chem‐ iochins and citochines) directed at the circulating inflammatory cells. In addition to this quota of growth factors, produced *ex-novo*, the main part of the muscle tissue contains growth factors stocked in active form inside its ECM, ready to be used in cases of urgent necessity; like for example in the repair of a lesion. (Ragk and Kerbel, 1997). In the case of tissue injury the capacity of biological tissue repair depends on the release of the activation of the growth factors ECM-dependent (or to the growth factors tied to the ECM) and of their capacity to start repair processes (Ragk and Kerbel, 1997). In particular, direct evidence exists that the Tumor Necrosis factor-α (TNF-α) covers and important physiological role in the repair process of the injured skeletal muscle, which is shown by the fact that, if its activity is inhibited during the healing process, there is a slight deficit of the repair capacity of the skeletal muscle itself (Warren et al., 2002). In addition, a large number of growth factors and citochine, as member of the family of Fibroblastic Growth Factors (FGF) of Insulin-Like Growth Factors (IGF), and of the family of Transforming Growth Factors-β (TGF-β), the Hepatocyte Growth factors (HGF), the Interleukin 1β (IL-1β) and the Interleukin-6 (IL-6), are amply known for their expression during muscular injury. After all it is also certain that many other factors, like the Plateled –Derived Growth-Factors are present in the course of various stages which are registered in a muscular injury (Mishra et al., 1995; Burkin and Kaufman, 1999). We should also note the fact that their expression may be induced, in the field of the skeletal muscle by physiological stimuli similar to those which cause micro-traumatic lesions, such as the phenomena of overstretching, or those relative to non-appropriate external mechanical loads (Burkin and Kaufman, 1999; Perrone et al., 1995). Considering the fact that these growth factors make up powerful mytogenic activators for numerous types of cells, it is now an acquired fact that the latter may also be involved in the activation of regenerative processes of the injured skeletal muscle (Burkin and Kaufman, 1999; Best et al., 2001; Chargè and Rudnicki, 2004). A certain number of these growth factors, like FGFs, IGF1, IGF2, TGF-β, HGF. TNF-α and the IL-6,are potential activators of the proliferation of the myogenic precursor cell (MPC,Myogenic Precursor Cells or satellite cells) (Chargè and Rudnicki, 2004). Some of these are also powerful stimulators for the differentiation of the MPC and after, in the course of regenerative processes, regarding the fusion of myotubes in multi-nuclear mature myo-fibers (Burkin and Kaufman, 1999; Best et al., 2001; Chargé and Rudnicki, 2004). In the acute phase, following a harmful muscular event, the polymorphonuclear leukocytes are the most abundant cells present on the injured area (Hurme et al., 1991; Thorsson et al., 1998; Brickson et al., 2001; Schneider et al., 2002; Bricksona et al., 2003) but, before the first day, the latter are substituted by the monocytes. In relation to the basic principles of an inflammatory process, these monocytes are eventually transformed into macrophages, which are employed in proteolysis and phagocytosis of the necrotic material, thanks to the release of lysosomal enzymes (Hurme et al., 1991; Best and Hunter, 2001; Farges et al., 2002 ; Timballi, 1995) The phagocytosis on behalf of the macrophages depending on the necrotic material, makes up a highly specific process. In this phase the intact

cylinders of the basal lamina, surround the necrotic part of the survived cells which have been left intact by the macrophages attacks and which, consequently, will be used as a scaffold inside which the satellite cells, able to survive, will start the formation of new myofibres (Grounds, 1991; Hurme and Kalimo, 1991; 1992). A fascinating demonstration of the incredible exactness and of its high biological co-ordination of this process, is given by the fact that the macro‐ phages, at the same time that they phagocyte the necrotic residue that surrounds the satellite cells, simultaneously send specific survival factors to the satellite cells themselves (Chazaud et al., 2003). It is also important to remember how the trauma involves a contextual breakage of the sarcoplasmatic reticulum and a consequent leakage of the calcium ions contained in it. The drastic increase of calcium ions inside the muscular fiber determines, in the 24-48 postlesion hours, a reflex contraction of the myofibrils inside and around the injured area. This phenomena involves an auto worsening phase of the injury prolonged in function of the period of muscular reflex contraction due to the phase defined by the name of "calcium overload"

Etiology, Biology and Treatment of Muscular Lesions

http://dx.doi.org/10.5772/56602

33

A few hours from the injury, the consumption of oxygen at rest, inside the injured muscular area, rises drastically, generating as a consequence an imbalance between the storing and the request of O2, which in its turn determines a rapid descent in the tension of O2 inside the injured area. Contextually to this, we assist in an increase in the concentration of lactate inside the lesion. All this series of events is well shown in the process of repair tissue in the ear of the rabbit observed at 15 days from the traumatic event(Hunt and Hussain, 1993) At the moment in which the tension of the O2 falls, the process of accumulation of lactate starts (Wasserman et al., 1990); to this end it is important to remember that the muscle produces a superior quantity of lactate than that which it consumes, in all conditions, including at rest (Graham et al., 1986). In this physiological context, the lactate assumes a sort of "guide role", inducing the fibroblasts to produce collagen and influencing the macrophages, and eventually also the lymphocytes, to excrete angiogenic substances. The repair components which we could describe as "lactate-guided" would seem to assume an even further importance, above all at the moment in which the inflammatory component diminishes notably, or starting, approxi‐ mately, from the seventh post-lesion day (Hunt and Hussain, 1993). The accumulation of lactate in the injured area is substantially ascribable to three factors. The first of these is made up of the fact that the vascular damage, following the tissue damage, inhibits the diffusion of O2 inside the injured tissue, from this follows a quota of lactate which is produced by anaerobic glycolysis (Im and Hoopes, 1970a: 1970b). The second of these, the vascular damage limits the external diffusion of lactate (Hunt et al., 1967) and the last reason, fact which makes up the most important aspect, is the activation of the leucytes which causes the release of a large quantity of lactate, both of hypoxic nature and not (Calwell et al., 1984). The macrophages which appear on the site of lesion a few hours before the harmful event- playing the role of "guided cells" in the field of the first repair processes they are not only able to supply the injured area with lactate, but are also influenced by the quota of lactate present. In fact,

(Armstrong et al., 1991a) which we have amply spoken about previously.

**22. The role of lactate in the process of muscular healing**

cylinders of the basal lamina, surround the necrotic part of the survived cells which have been left intact by the macrophages attacks and which, consequently, will be used as a scaffold inside which the satellite cells, able to survive, will start the formation of new myofibres (Grounds, 1991; Hurme and Kalimo, 1991; 1992). A fascinating demonstration of the incredible exactness and of its high biological co-ordination of this process, is given by the fact that the macro‐ phages, at the same time that they phagocyte the necrotic residue that surrounds the satellite cells, simultaneously send specific survival factors to the satellite cells themselves (Chazaud et al., 2003). It is also important to remember how the trauma involves a contextual breakage of the sarcoplasmatic reticulum and a consequent leakage of the calcium ions contained in it. The drastic increase of calcium ions inside the muscular fiber determines, in the 24-48 postlesion hours, a reflex contraction of the myofibrils inside and around the injured area. This phenomena involves an auto worsening phase of the injury prolonged in function of the period of muscular reflex contraction due to the phase defined by the name of "calcium overload" (Armstrong et al., 1991a) which we have amply spoken about previously.
