Pavan Jain, INFS alumini
Circadian rhythm is body’s internal 24 hour clock which cycles between sleep and alertness depending on the time of the day. Insufficient sleep for a prolonged period of time, affects the circadian rhythm leading to adverse health effects. Sleep deprivation is common in working conditions with rotating shifts or prolonged work hours. Circadian rhythm mainly influences hormone release, exercise and feeding patterns, and body temperature. The Circadian clock significantly affects skeletal muscle metabolism. Entrainment of skeletal muscle circadian rhythms may also contribute to systemic health. A significant association has been reported between irregular sleep pattern and autoimmune hypothyroidism. Hypothyroidism is a condition in which the body lacks sufficient thyroid hormone. Thyroid gland regulates metabolism, hence people with under active thyroid have a slow metabolism leading to weight gain and fatigue due to muscle loss. Loss of muscle protein is detrimental to a person’s health. The aim of this article is to review the literature on the effects of the circadian rhythm on muscle metabolism and hypothyroidism.
Circadian rhythms are physical, mental and behavioural changes that follow a 24-hour cycle (Figure 1), responding primarily to light and darkness in an organism’s environment. Various physiological functions, including the sleep wake cycle, body temperature, hormone secretion, and locomotor activity, exhibit circadian rhythms. This time-dependent regulation is driven by an internal circadian clock . In addition to maintaining rhythmicity in nearly every cell of the body, these clock factors also mediate tissue specific metabolic functions. Disruption to rhythms usually have a negative effect to the body, an individual may experience fatigue, disorientation and insomnia.
Skeletal muscle, similar to every organ/tissue in the body, has circadian rhythms. Circadian rhythms and the molecular clock mechanism modulate the expression of a substantial number of genes in skeletal muscle, many of which participate in transcription, myogenesis, and
metabolism . Skeletal muscle is the most abundant tissue in the human body, comprising approximately 45% of total body mass. Skeletal muscle tissue is an intricate network of more than 600 individual muscles that have different fiber-type compositions, metabolic capacities, and mechanical functions . There is a strong co-relation between muscle composition and circadian rhythm. Disruption of circadian rhythm leads to impaired muscle function, muscle loss, weight gain and disease development. Hence, skeletal muscle tissue and circadian rhythm are critical for both muscle and systemic health.
Figure 1: Circadian clock
Irregular sleep patterns is commonly seen in the modern society due to night shift work or prolonged work hours or chronic jet lag in frequent travellers. Sufficient sleep each night for about 7-8 hours is essential for maintaining circadian rhythm and good health . Immune response is affected due to sleep loss leading to detrimental effects on health.
Circadian and sleep components modulate anterior pituitary release of thyrotropin (TSH), the chemical substance regulating the thyroid hormones (Figure 2), thyroxine (T4), and triiodothyronine (T3). Sleep deprivation disrupts the circadian rhythm and may produce substantive changes in the thyroid axis .
Figure 2: Thyroid Hormones
Hypothyroidism is a condition occurring due to thyroid hormone deficiency. Thyroid glands are responsible for the metabolism of the body. Any alterations of the thyroid function could have an impact on the metabolism eventually leading to conditions associated with slow metabolism such as obesity, muscle loss, fatigue etc .
Circadian Rhythm relationship with Muscle Metabolism and Hypothyroidism:
The classic phase markers for measuring the timing of human’s circadian rhythm are; 1) melatonin secretion by the pineal gland , 2) core body temperature minimum  and 3) plasma level of cortisol .
Melatonin is a hormone secreted by the pineal gland in the brain. It helps regulate other hormones and regulates sleep and wakefulness maintaining the body’s circadian rhythm (Figure 3). Circadian rhythms are important in determining human sleep patterns. Circadian clock is divided into two parts- the master clock and the peripheral clock . The body’s master clock in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clock in the peripheral tissues, such as the liver, skeletal muscle and so on, as well as brain areas other than the SCN.
The SCN receives information about illumination through the eyes. When there is low light during night, the SCN sends information to the brain to produce more melatonin to make the body drowsy. Smartphone utilization during night has a negative impact on sleep . It is considered that reduction of melatonin secretion under the blue light exposure from smart- phone displays blue light causing reduction in melatonin secretion. Destruction of the master clock results in the complete absence of a regular sleep–wake rhythm affecting the immunity.
Figure 3: Melatonin levels at different time intervals
Molecular Clock and the Skeletal Muscle
The peripheral clock regulates muscular biological functions. Scheduled exercise can entrain the circadian clocks in skeletal muscles . Skeletal muscle and bone have roles in not only the regulation of locomotion and postural support but also the control of nutritional homeostasis, such as maintaining glucose and calcium levels. Feeding and exercise stimulate these tissues and change their functions, including the maintenance of tissue mass and metabolism .
Core Body Temperature
The average human adult’s temperature reaches its minimum at about 5 am, about two hours before habitual wake time. However, newer research indicates that the melatonin offset may be the more reliable marker. Benloucif et al.  found that melatonin phase markers were more stable and more highly correlated with the timing of sleep than the core temperature.
Cortisol- The Stress Hormone
Normally cortisol levels are highest in the morning (Figure 4), which gives the body good amount of energy to be active the whole day and lowest in the night which helps the body to fall and stay asleep. Insufficient sleep affects the cortisol levels and weakens the adrenal glands. Weak adrenal glands lead to a state of catabolism, in the process the body tries to slow down the metabolism which is accomplished by thyroid gland. Hence weak adrenal glands affect the immunity  and lead to hypothyroidism.
Figure 4: Cortisol levels at different time intervals
Circadian Clock in Muscle Mass and Muscle Strength
A study showing disruption in circadian clock reported an increase in muscle weight and a decrease in muscle strength, although the whole body exhibited muscle loss. This indicates that while a circadian clock during development regulates muscle mass, an intrinsic skeletal muscular clock may not directly regulate it. Lack of muscle use and the lowering of daily locomotor activity levels reduce muscle mass . Another study showed increase in muscle mass, have a normal circadian rhythm . These data suggest that physical activity affects muscular clocks. Physical activity causes several physiological changes, such as to body temperature and hormonal status, which are known to affect the peripheral clocks . Hence the growth of the skeletal muscle depends on the circadian clock-regulated activity levels. Scheduled exercise can entrain the circadian clocks in skeletal muscles , i.e., the phase of rhythmic gene expression in skeletal muscle may be regulated by the rhythm of locomotor activity. The potential impact physical activity may have as an entrainment cue for skeletal muscle suggests that entrainment cues for skeletal muscle may be useful as therapies in conditions of circadian disruption .
Recent studies have begun to demonstrate that disruptions in circadian rhythms can be detrimental to skeletal muscle health causing impaired muscle function, reduction in muscle mass and muscle strength, eventually leading to muscle loss and weight gain .
Effect of Feeding Time on Muscular Circadian Clock
The peripheral clocks are synchronized by the central clock, but they can also be influenced by behaviour, such as feeding or exercise. Feeding/fasting is considered as one of the time cues to synchronize the skeletal muscle clock. For instance, during the fasting period, glucose
availability is low and the skeletal muscle must alter substrate metabolism accordingly . If skeletal muscle rhythms are disrupted or asynchronous, entrainment cues may be a useful strategy in resetting the skeletal muscle clock so that it is both entrained to the environment and in synchrony with other tissue rhythms. This suggests that, at least in the muscle, it is not the food consumption, but rather the fasting which exhibits an inhibitory effect on muscle specific rhythmic genes, leading to resetting of the muscle clock .
Sleep deprivation and Thyroid Hormone
Stress induces autoimmune disorders by affecting the immune response modulation. Low serum cortisol level is associated with autoimmunity like Hashimoto’s thyroiditis with hypothyroidism. Recent studies have shown that irregular sleep pattern induces stress that enhances the onset of the autoimmune hypothyroidism . Lack of sleep raises inflammation, which can worsen Hashimoto’s hypothyroidism.
Thyroid hormone activity sharply increases when an individual is in a state of sleep deprivation. During sleep deprivation, the hypothalamic-pituitary-thyroid axis initially increases as a consequence of increased release of thyroid stimulating hormone from the pituitary. Subsequently, as sleep deprivation continues, the sympathetic nervous system is recruited through its anatomical connection with the thyroid gland. Thyroid stimulating hormone levels markedly increase during sleep deprivation. The physiology of the thyroid axis during sleep deprivation and the actions of the effector hormone thyroid hormone suggest that thyroid hormone inhibits sleep .
Regulation of Disrupted Circadian Rhythm
Following are the different ways to regulate the misaligned Circadian Rhythm-
1. Exercise/Weight Training: Weight training or resistance training helps in regulating the circadian rhythm to great extent. Exercises are important for the maintenance of homeostasis in the skeletal muscle. Weight training would help recover the lost muscle mass and muscle strength. Exercise can prevent circadian disturbance-induced muscular dysfunctions.
2. Scheduled Eating: Time of food intake is emerging as a dominant agent that affects circadian clocks in metabolic organs . Scheduled eating combined with a nutritious diet has a great impact on regulation of the rhythm and also helps overcome sleep deprivation.
3. Avoid Blue Screen: Blue light (Figure 5) which is emitted from electronic devices (laptop, e readers, and smart phones) has a very powerful effect on master clock . This in turn
affects the melatonin production causing delay in sleep cycle or affects quality sleep. Hence it is recommended to avoid using electronic devices during bed time.
Figure 5: Blue screen
4. Avoid dim light in the daytime or bright light in the night: People working in closed cabins may not be exposed to bright light, hence affects the internal body clock and makes an individual feel drowsy during day time. On the contrary excessive bright light during evening or night time keeps the body awake.
5. Avoid Caffeine or caffeinated drinks few hours prior to sleep time.
6. Refer a sleep specialist: People suffering from chronic sleep deprivation (disrupted rhythm) despite following the above methods, are recommended to consult a sleep specialist.
In today’s modern society due to nocturnal working hours, prolonged work hours, frequent travelling, stress etc has led to disruption in the circadian rhythm. Lack of quality sleep or irregular sleep pattern has brought about misalignment in the circadian rhythm. This further affects the immunity leading to a lot of systemic diseases. This article reviews the effect of circadian rhythm on muscle metabolism and hypothyroidism. Hypothyroidism being one of the disease caused due to low immunity is found to be prone in individuals lacking sleep due to stress and causing disturbance in the circadian rhythm. Disruption in Circadian rhythm leads to muscle loss and hence, weight gain. Many diseases are associated with altered muscle mass, function and metabolism, hence the disturbances in circadian rhythm has to be corrected. Muscle recovery can be made by weight training to build up the muscle mass and lose fat. Scheduled exercise and scheduled feeding and monitoring eating pattern is an important aspect of lifestyle. Improvement in lifestyle would have a great impact in
preventing or managing the disrupted circadian rhythm, before the body is affected by any of the systemic diseases.
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