**3.1 Muscle fatigue**

It is well known that muscle performance may decline with prolonged or intense muscle activity, especially if there is a shortage of 02 (Allen et al. 1995; Westerblad et al. 2002). This decline is known as muscle fatigue. The causes of fatigue are probably multiple, but the consequence is that the power output may be drastically reduced. The consequence of lost power is obvious during sporting activity, for example, in endurance sports. It is almost impossible to maintain a marathon race if the muscles are exhausted. When a muscle goes from rest to high-intensity exercise a marked acidification occurs because of the shortage of 02. The energy demand exceeds the capacity from available aerobic metabolism. The metabolism will enter the anaerobic pathway and the ATP required will come from anaerobic metabolism. Anaerobic breakdown of glycogen leads to intracellular accumulation of inorganic acids such as, for example, lactic acid. Lactic acid is a strong acid and dissociates easily to lactate and H+ at physiological temperature. Lactate might therefore have limited effect of its own on the muscle contractions. The traditional thinking was that H+ is produced together with lactate, and H+ created the pH change and was the important cause of fatigue.

Recently presented data provide substantial support for that increased inorganic phosphate (Pi) having a key role in muscle fatigue (Westerblad et al. 1991; Westerblad et al. 1998; Westerblad 2002; Westerblad & Allen 2003), especially at physiological temperature (Westerblad et al 1997). For acidosis, on the other hand, most recent data indicate that its depressive effect on muscle contraction is limited. Other studies express doubts about the effect of Pi, and indicate that it is too early to dismiss H+ as an important factor in muscle fatigue (Fitts 2003).

The way in which human uterine smooth muscle cells metabolize and meet the energy demands during labor is still obscure. Energy is produced by glycolysis, ending with the formation of ATP and pyruvate. It has in different studies been demonstrated that the human uterus utilizes glucose as its main energy substrate at term pregnancy. It seems that smooth muscle cells in uterus are capable of producing lactate at a higher rate under aerobic conditions compared with striated muscle cells.

Fatigue has many sources that may be present in different sites in the muscle cells (Taggart & Wray 1998). Many constituents of muscle metabolism change during fatigue and for each of these metabolites we need to know which role they have in the regulation of the muscle contraction. Despite nearly 200 years of muscle function research, the question of muscle fatigue still remains partly unresolved.

#### **3.2 Lactate shuttles**

Earlier, lactate was considered to be transported across the membrane only via passive diffusion, depending on a pH gradient, (Crone 1963; Brooks 2002; Philp et al. 2005). Subsequent publications revealed a carrier-mediated transport of lactate across membranes. An entire family of monocarboxylate transport proteins (MCT), which facilitate the transport of lactate in and out of the cells, has been described (Bonen et al. 1997; Brooks et al. 1999; Bonen 2000; Bonen 2001). During exercise lactate and H+ move in and out of tissue primarily via MCT1 and MCT4, diffusion of undissociated lactate constitutes a smaller component of the transport. It has been proposed that the force of smooth muscle contractions during labor is reduced by hypoxia in uterus, and studies have pointed out that myometrial lactic acidosis is associated with dysfunctional labors.

Lactate exchange is a dynamic process with simultaneous uptake and release between cells at rest and during exercise. At rest muscles slowly release lactate in to the surrounding fluids on a net basis, but cells may also show a small net uptake. During exercise, muscle tissue produces lactate rapidly. This results in an increased intracellular concentration of lactate and an increased net output of lactate from the muscle cells to the surrounding fluids. During recovery there is a net uptake of lactate from the ambient fluid by resting muscles, or other muscles that are exercising at low or moderate intensity. During prolonged exercise of low to moderate intensity, the muscles that originally released lactate on a net basis at the onset of exercise may actually reverse it to net lactate uptake. The conclusion from many recent studies is that lactate is a useful metabolic intermediate which can be exchanged rapidly between tissue compartments (Brooks 2002). Lactate can also be used as a substrate in aerobic condition.
