December 30, 2023

Muscle Strength Depends on Circadian Rhythm.

 

Muscle building and repair 

Strong muscles day and night 

 

Healthy foods eaten in a window of 6 to 10 hours per day limit insulin production and allow HSL (Hormone Sensitive Lipase), an enzyme, to “cut” (cleave) long chain fats into small pieces of fat called triglycerides. HSL “opens the door” of fat cells to release fats. Fats (fatty acids) exit the fat cells and travel via circulation to muscle cells. Muscles burn fats for energy production during the day and especially at night via oxidative metabolism. Muscles repair and build at night. ATP energy is produced in abundance via fat burning in muscles. 

 

 

 

 

Muscles are repaired and built while we sleep if we fast for 14 to 18 hours via water only fasting at night.  

 

 

Weak muscles 

 

Eating in a window longer than 10 hours per day and/or eating greater than 30 to 40% of energy intake (calories) as carbohydrates causes the pancreas to be overworked. In stage 1 of insulin resistance, the still healthy pancreas produces way too much insulin.

High insulin production raises insulin levels and inhibits the enzyme HSL (Hormone Sensitive Lipase). That is why it is called hormone sensitive lipase, because it is sensitive to how much insulin is around. 

Because HSL, the enzyme that allows fats to leave fat cells, is turned off by insulin, fats become trapped in fat cells. The result is excess insulin “shuts the door” of the fat cells and fats cannot leave the fat cells to be burned by muscles. 

Muscles are deprived their preferred energy source which is fats. Muscles waste away. 

Meanwhile in the face of high insulin production more fats are made in the liver and sent to the fat cells to be stored. 

In the final stage, the swollen pancreas Beta cells eventually become exhausted from being over worked; they shrink and produce less insulin, but it is still enough to block HSL from working. However, it is not quite enough insulin to allow all the excess sugar to enter cells. Blood sugar rises leading to metabolic syndrome, prediabetes, and type 2 diabetes. Fats continue to enter the fat cells. 

 

Fat cells continually store fats due to prolonged eating and/or excess carb intake. High insulin levels shut the HSL door so fats cannot leave fat cells. Muscles are deprived of energy from fats and waste away. 

 

Stage 1 of insulin resistance deprives muscles of their preferred energy source, fats. 

 

 

Final stage of insulin resistance deprives muscles of their preferred energy source, fats. 

 

 

How do we know we have our own internal circadian clock rhythm? 

 

We know our rhythm is our own internal biological clock because when we are removed from our environment and moved to a different environment, the rhythm and the cyclic behaviors and processes it controls continue on their own. This is true for plants, animals, and humans.

The first famous experiment that pointed to plants having their own internal clock(s) was done by an astronomer, Jean Jacques d’Ortous de Mairan. He noticed that the leaves of mimosa plants opened toward the sun during day and closed and drooped at night.

He wondered what would happen if he placed the plant in a dark cabinet. He was surprised to find that the leaves of the plant continued to unfold and then fold and droop even if the plant did not have any light. The plant continued its 24-hour routine as if it had its own internal clock. What makes our human circadian clock rhythm so elegant is that over time our circadian rhythm can reset if we move to a new time zone. It adjusts to connect us to our new environment. 

 

Circadian clockwork --- 2017 Nobel Prize 

 

While we have known for years that we have a circadian rhythm and it helps us to anticipate and adapt to our environment, how the clock worked was not known until 2017. The Nobel Prize in Physiology or Medicine was awarded to Jeffrey C Hall, Michael Rosbash, and Michael W. Young when they discovered the way we adapt our biological clock rhythm and synchronize it to the Earth’s revolutions. 

The Nobel Prize winners isolated the gene for the circadian rhythm. The gene was given the name PERIOD. They went on to show that the PERIOD gene produces a protein named PER during the night that then degrades in quantity during the day. Finally, they showed that high levels of PER block the gene PERIOD which creates an automatic feedback system where high levels of PER prevent its own synthesis. Thus, the quantity of PER protein oscillates over 24 hours in sync with the circadian rhythm. 

The next mystery they solved was this: The PERIOD gene is in the nucleus of the cell where m-RNA is made from it. The m-RNA moves out of the nucleus to the cytoplasm of the cell where PER protein is made from it. So, the question was how did PER protein move back into the nucleus of the cell to inhibit PERIOD gene in the nucleus? Michael Young discovered another clock gene TIMELESS which encodes to make a protein call TIM that is required for circadian rhythm. He discovered that when TIM binds to PER, together the 2 proteins can enter the nucleus of the cell and inhibit PERIOD gene creating the feedback loop for our perpetual circadian clock. 

One ultimate question was what controlled the frequency of the oscillations? Michael discovered yet another clock gene called DOUBLETIME that codes to make a protein called DBT that helps match the oscillations to 24 hours. 

Later, our exposure to light (especially bright light and blue light) was discovered to further fine tune the synchrony of our circadian clock. After these discoveries, circadian science developed into a vast field with rich rewards related to our health and wellbeing. 

 

The time of day influences how well medication works. 

We do not know all the reasons why. 

Time of day is rarely considered in medical practice. 

 

The number one selling family of drugs called statins, for example Lipitor (atorvastatin), used to control cholesterol and blood fats do so by inhibiting an enzyme that has a circadian rhythm. This family of drugs is more effective if taken in the evening than in the morning. Simvastatin (Zocor) was first approved for once a day dosing in the evening, but evening dosing is no longer required in its labeling. Scant prescriptions for this mega family of drugs are written for evening dosing. The FDA does not require statins to be labeled for evening dosing. Ruben, M “Dosing Time Matters” 2019 Science (2044) 

We know that steroid medications (glucocorticoids) like prednisone are best taken in the morning for conditions like arthritis, asthma, and seasonal allergies. This is because taking the steroid in the morning mimics the body’s morning peak of cortisol steroid hormone production in the natural circadian rhythm. Taking steroids multiple times per day or around the clock violates the natural hormone production rhythm and depending on the dose can even blunt natural production of cortisol steroid family of hormones. 

Certain chemotherapy drugs work better if infused at night. Some chemotherapy is more effective if taken when fasting. 

Time of day and circadian rhythm are rarely considered when medical orders are written. Health care providers administer drugs based on staffing levels, timing of when doctors make rounds in the hospital, workload at varying times, convenience, and as needed. However, over 100 published studies indicate that the time of day when a drug is given matters. Yet very little of this has transferred to clinical practice in the field. Only a small handful of the most common drugs have time of day labeling (4 of the top 50 drugs). An animal study found most of best-selling drugs in the US and drugs on the World Health Organization essential medicines list directly target the products of rhythmic genes. (2048)

There is a great deal of evidence that our molecular clocks coordinate circadian rhythms of our heart, hormones, metabolism, immune system, and behavior. Molecular clocks are pervasive in our bodies. Over 50% of our protein coding genes having a circadian rhythm. Virtually every cell has clock genes. What it is coming down to is circadian regulation is a property of most body systems. About 1 out of every 8 circadian cycling genes is a known drug transporter or drug target gene. The goal of circadian medicine is to raise awareness and apply what is known about biological rhythms that occur every 24 hours to drug therapy. Ruben, M “Dosing Time Matters” 2019 Science (2044) 

 

Medications where time of day taken was

important. 

 

 

 

 

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