**4.1 Mechanism of muscle loss under microgravity**

The first muscular measurements were performed in Skylab and Space Shuttle missions by the United States and in Salyut and Mir by the Soviet Union [34–37]. The most prominent muscle loss was observed in the calf muscle (the soleus and gastrocnemius) after a few weeks in space. The muscle loss exhibited interindividual variation, but the maximum loss reached as high as 10%. This volume loss in the lower extremities accounts for most of the muscle atrophy and the blood and interstitial fluid shift. Although fluid shift away from the legs influences the size of these muscles, this phenomenon alone cannot explain the changes in leg volume on MRI. Muscle atrophy appears rapidly, usually between 8 and 11 days of flight,

but can appear as early as the fifth day, as observed in one astronaut. Moreover, the effects of microgravity differ among muscles, with volume decreasing by 3.9% in the calf (the soleus and gastrocnemius) and 6% in the quadriceps femoris.

In addition to the morphological changes, functional alterations are associated with structural variations, and the muscular force is known to be reduced after spaceflight. In the Skylab 3 mission, it decreased by 20% after 53 days of microgravity exposure. Muscular electrical activity measured by electromyogram (EMG) had a lower EMG amplitude in addition to easy fatigability with a lower resistance.

The main cause of muscular loss is the disappearance of mechanical constraints and the subsequent decrease in muscular activity. The reduced muscular activity under microgravity is also associated with hypokinesia due to limited movement inside the spacecraft, which also can be observed in bedrest studies and animal experiments using tail suspension. The structural changes in skeletal muscle are also observed by microscopic examination under microgravity, which revealed that the proportion of type I red fibers decreased and they were replaced by type II white fibers. In 1995, pre- and postflight human muscle biopsies were performed on three and five astronauts during 5- and 11-day missions, respectively. In this study, the muscle fiber diameter decreased by 15 to 30%, and the number of capillaries around the muscle fibers decreased. The proportion of type I fibers changed from 43 (preflight) to 37% (postflight) after 5-day missions, and that of type II fibers changed from 57 to 67%. After 11 days of spaceflight, the proportion of type I fibers decreased from 45 to 39%, and that of type II fibers decreased from 55 to 61%, consistent with the animal experiments that demonstrated that gravity can influence genes regulating the protein synthesis of muscle protein degradation enzymes.

These changes were confirmed to be due to both an increase in protein breakdown and decrease in synthesis. Human biochemical examination also revealed a higher level of muscle protein degradation, increased level of urinary amino acids, and higher level of creatinine. The diet of astronauts is protein-rich, but the degradation process is such that nitrogen losses overcome the gains and the nitrogen balance becomes negative.

Recent studies have suggested the mechanism of disuse atrophy of the skeletal muscle, especially oxidative stress, to be an important regulator of pathways leading to muscle atrophy during periods of disuse. Redox disturbances, such as those in skeletal muscle myotubes, increase the expression of key components of the proteasome proteolytic system, which is a prominent factor in protein degradation in disused muscles.

Another hypothesized mechanism is the degradation of muscle proteins resulting from their ubiquitination. These molecular mechanisms underlie protein degradation during disuse.

#### **4.2 Countermeasures for muscle loss**

In order to prevent muscle loss, several countermeasures were available during microgravity exposure in Shuttle missions and continue to be available on the ISS. These include aerobic exercise, stretching, strength training, and electrical stimulation. Artificial gravity with exercise has been proposed as a potential measure for muscle loss because ground-based studies confirmed it to be effective, but a short-arm centrifuge has not been mounted. In addition to physical stimulation, medications, such as antioxidants, growth hormone, growth factors, ubiquitin, clenbuterol, anabolic steroids, and amino acids, are candidates against muscle loss.

Aerobic exercise is the most effective countermeasure for maintaining the fast twitch red fibers. On the ISS, the combination of an ergometer, treadmill, and the Advanced Resistive Exercise Device (ARED) is ideal to maintain muscle power and

**21**

*Effects of Microgravity on Human Physiology DOI: http://dx.doi.org/10.5772/intechopen.90700*

it is a valid countermeasure considering human physiology.

the decrease in oxidative enzymes inducing disuse atrophy.

**4.3 Artificial gravity with exercise**

gastrocnemius [38].

**5. Bone metabolism system**

bone formation and absorption are described.

short for receptor activation of NF-kappa B ligand).

**5.1 Bone development and restructuring**

bone strength, leading to fractures.

most recommended exercise for resistance training is squatting.

fiber muscles).

the morphology of antigravity muscles (empowerment of both fast and slow twitch

Strength training by resistance exercise is also employed as a countermeasure for muscle loss. Weight training studies recommended a good mix of exercise types to be 15% (eccentric), 10% (isometric), and 75% (concentric weight-bearing). The

Electric stimulation is also expected to increase protein synthesis and prevent

We previously confirmed the effectiveness of artificial gravity in bedrest studies

[33]. Our results demonstrated that artificial gravity of 1.4 G with ergometric exercise maintains the muscle strength and cross-sectional area of the quadriceps femoris measured by MRI. Another study revealed that artificial gravity with squatting exercise also maintains the function and morphology of the soleus and

The main problem of the skeletal system is bone calcium (Ca2+) loss during microgravity. The bone becomes fragile during microgravity exposure, which can harm an astronaut or cosmonaut even after returning to Earth. Moreover, the risk of

Ca2+ plays an essential role in bone structure, contraction of skeletal and cardiac muscles, neural transmission, blood coagulation, cell permeability, and hormonal signaling. The serum Ca2+ level is well maintained at 8.4–10.2 mg/dL. Ca2+ is absorbed from the small intestine (300 mg/day), into the blood, deposited in the bone (500 mg/day), and excreted from the kidneys (150 mg/day) or into feces. In this section, the influences of gravity on bone structure and of hormones on

Gravity influences the long bones of the lower extremities, e.g., the femur, tibia,

calcaneus, and vertebrae, which support the body in the upright position. Bone tissue contains osteocytes, which develop from osteoblasts, and are changed into osteoclasts by the action of RANKL (also called osteoclast differentiation factor,

Osteoblasts and osteoclasts are functionally closely related, as is the balance between bone formation and bone resorption. Thus, insufficient bone formation compared with bone resorption observed in spaceflight reduces the bone mass and

renal stones is high during long-term missions due to hypercalcemia [39].

Stretching can minimize atrophy by maintaining the muscle as much as possible in the stretched condition. In the Russian space program, the penguin suit—a snug fitting, full-length, long sleeved jumpsuit made with elastic inserts at the collar, waist, wrists, and ankles and along the vertical sides of the suit—loads the body along the long axis with an adjustable force of 15–40 kg, while the other elastic elements make it possible to adjust the position of the limbs. The angle of the major joints, such as the knee and ankle, can be set, allowing the foot to be dorsiflexed, which will stretch the soleus. The effects of stretching are not well understood, but

### *Effects of Microgravity on Human Physiology DOI: http://dx.doi.org/10.5772/intechopen.90700*

*Beyond LEO - Human Health Issues for Deep Space Exploration*

but can appear as early as the fifth day, as observed in one astronaut. Moreover, the effects of microgravity differ among muscles, with volume decreasing by 3.9% in the calf (the soleus and gastrocnemius) and 6% in the quadriceps femoris.

In addition to the morphological changes, functional alterations are associated with structural variations, and the muscular force is known to be reduced after spaceflight. In the Skylab 3 mission, it decreased by 20% after 53 days of microgravity exposure. Muscular electrical activity measured by electromyogram (EMG) had a lower EMG amplitude in addition to easy fatigability with a lower resistance.

The main cause of muscular loss is the disappearance of mechanical constraints and the subsequent decrease in muscular activity. The reduced muscular activity under microgravity is also associated with hypokinesia due to limited movement inside the spacecraft, which also can be observed in bedrest studies and animal experiments using tail suspension. The structural changes in skeletal muscle are also observed by microscopic examination under microgravity, which revealed that the proportion of type I red fibers decreased and they were replaced by type II white fibers. In 1995, pre- and postflight human muscle biopsies were performed on three and five astronauts during 5- and 11-day missions, respectively. In this study, the muscle fiber diameter decreased by 15 to 30%, and the number of capillaries around the muscle fibers decreased. The proportion of type I fibers changed from 43 (preflight) to 37% (postflight) after 5-day missions, and that of type II fibers changed from 57 to 67%. After 11 days of spaceflight, the proportion of type I fibers decreased from 45 to 39%, and that of type II fibers decreased from 55 to 61%, consistent with the animal experiments that demonstrated that gravity can influence genes regulating the protein synthesis of muscle protein degradation enzymes. These changes were confirmed to be due to both an increase in protein breakdown and decrease in synthesis. Human biochemical examination also revealed a higher level of muscle protein degradation, increased level of urinary amino acids, and higher level of creatinine. The diet of astronauts is protein-rich, but the degradation process is such that nitrogen losses overcome the gains and the nitrogen

Recent studies have suggested the mechanism of disuse atrophy of the skeletal muscle, especially oxidative stress, to be an important regulator of pathways leading to muscle atrophy during periods of disuse. Redox disturbances, such as those in skeletal muscle myotubes, increase the expression of key components of the proteasome proteolytic system, which is a prominent factor in protein degradation

Another hypothesized mechanism is the degradation of muscle proteins result-

In order to prevent muscle loss, several countermeasures were available during microgravity exposure in Shuttle missions and continue to be available on the ISS. These include aerobic exercise, stretching, strength training, and electrical stimulation. Artificial gravity with exercise has been proposed as a potential measure for muscle loss because ground-based studies confirmed it to be effective, but a short-arm centrifuge has not been mounted. In addition to physical stimulation, medications, such as antioxidants, growth hormone, growth factors, ubiquitin, clenbuterol, anabolic steroids, and amino acids, are candidates against muscle loss. Aerobic exercise is the most effective countermeasure for maintaining the fast twitch red fibers. On the ISS, the combination of an ergometer, treadmill, and the Advanced Resistive Exercise Device (ARED) is ideal to maintain muscle power and

ing from their ubiquitination. These molecular mechanisms underlie protein

**20**

balance becomes negative.

degradation during disuse.

**4.2 Countermeasures for muscle loss**

in disused muscles.

the morphology of antigravity muscles (empowerment of both fast and slow twitch fiber muscles).

Stretching can minimize atrophy by maintaining the muscle as much as possible in the stretched condition. In the Russian space program, the penguin suit—a snug fitting, full-length, long sleeved jumpsuit made with elastic inserts at the collar, waist, wrists, and ankles and along the vertical sides of the suit—loads the body along the long axis with an adjustable force of 15–40 kg, while the other elastic elements make it possible to adjust the position of the limbs. The angle of the major joints, such as the knee and ankle, can be set, allowing the foot to be dorsiflexed, which will stretch the soleus. The effects of stretching are not well understood, but it is a valid countermeasure considering human physiology.

Strength training by resistance exercise is also employed as a countermeasure for muscle loss. Weight training studies recommended a good mix of exercise types to be 15% (eccentric), 10% (isometric), and 75% (concentric weight-bearing). The most recommended exercise for resistance training is squatting.

Electric stimulation is also expected to increase protein synthesis and prevent the decrease in oxidative enzymes inducing disuse atrophy.

## **4.3 Artificial gravity with exercise**

We previously confirmed the effectiveness of artificial gravity in bedrest studies [33]. Our results demonstrated that artificial gravity of 1.4 G with ergometric exercise maintains the muscle strength and cross-sectional area of the quadriceps femoris measured by MRI. Another study revealed that artificial gravity with squatting exercise also maintains the function and morphology of the soleus and gastrocnemius [38].
