Don’t be Late: The Importance of Timing in Musculoskeletal Health

At the Tendon and Joint Healing Academy, our mission is to empower highly motivated, active individuals with knowledge on their journey to healing and recovery from musculoskeletal injuries.

Steven Makovitch DO and Christine Eng MD

Objectives:

Understand the importance of proper circadian rhythms and the effects on musculoskeletal health

To do this we must:

• Define a circadian rhythm
• Understand light as a key zeitgeber
• Explore recent research findings related to circadian rhythms' impact on various tissues, such as the musculoskeletal system, and the mechanisms behind these effects

Give me the Easy Version…

Our bodies operate on a natural clock called the circadian rhythm, influenced by light and darkness. This rhythm is about 24 hours long and regulates various bodily functions. Humans have a highly specialized group of about 20,000 neurons in the brain which is our body's master timekeeper. This area is called the suprachiasmatic nucleus or SCN for short. The SCN responds to light cues received through our eyes.

Most people don’t know that there is also another timing system found within our cells. Cellular circadian clock genes are a group of genes that regulate the internal 24-hour rhythm of cells.  These genes like "CLOCK" and "BMAL1" act like a daily timer in our cells to orchestrate cellular processes, such as energy production. Light is the primary signal for these genes to operate optimally, but other factors like eating, resting, and body temperature also influence our body's timing.

Proper timing is crucial for our musculoskeletal health. Disrupted rhythms can lead to bone and cartilage issues. For instance, a disrupted circadian rhythm in shift workers is linked to bone density reduction and osteoporosis risk. Circadian rhythms even affect tendons, with some genes and proteins following a rhythm. A study showed how circadian disruptions affect collagen production and could contribute to conditions like tendinopathy.

Muscles are also affected. Disrupted circadian rhythms can lead to muscle atrophy and inefficiency in metabolic processes.

In essence, proper timing is essential for our musculoskeletal health. Factors like light, eating habits, and daily routines influence our body's internal clock. Maintaining a balanced circadian rhythm can help prevent bone, cartilage, and muscle problems.

Give me the details…deeper dive

Nearly all living organisms display circadian rhythms. Derived from Latin “Circa” meaning approximately and “diem” meaning day. Our normal circadian rhythms are approximately 24 hours long and influenced by proper light and dark cycles of day and night with the rotation of the earth. Humans have a highly specialized group of about 20,000 neurons in the hypothalamus which is our body's most significant master timekeeper. This area is called the suprachiasmatic nucleus or SCN for short. The SCN receives light information from intrinsically photosensitive ganglion cells of the retina via the retino-hypothalamic tract. The SCN then releases instructions to the paraventricular nucleus in the brain and the superior cervical ganglia in the neck which is then delivered to endocrine glands ². Basically, light thought the eye impacts the SCN and therefore our circadian timing.

³Ma Z, Yang Y, Fan C, et al. Melatonin as a potential anticarcinogen for non-small-cell lung cancer. Oncotarget. 2016;7(29):46768-46784

We also have a timing mechanism at the cellular level, including the musculoskeletal system. Cellular circadian clock genes are a group of genes that regulate the internal 24-hour rhythm of cells. They control the timing of cellular processes by producing proteins and molecules. The main clock genes include “CLOCK” and “BMAL1”, which work together to activate the transcription of other clock genes. The Period genes (PER1, PER2, PER3) and Cryptochrome genes (CRY1, CRY2) form a negative feedback loop by producing proteins that inhibit their own transcription. REV-ERB genes (REV-ERBα, REV-ERBβ) regulate gene expression and help control the timing of the circadian rhythm. These clock genes interact with each other to coordinate cellular activities, such as gene expression and metabolism, ensuring they occur at the right times of day ¹.

Light is the strongest zeitgeber, or time cue. Although, multiple other zeitgebers coordinate with light to optimize circadian tissue functions including eating/fasting, rest/activity, and body temperature ⁴. Everything in our body has a circadian mechanism and some normal functions are depicted below ². Circadian rhythms become disrupted with ageing, making it even more important to have appropriate timing mechanisms in our tissues as we get older⁴.

24 h circadian rhythm and human body response. The clock represents a 24 h clock time that uses the numbers 00:00 (midnight) to 23:59 to tell time

Juliana N, Azmi L, Effendy NM, et al. Effect of Circadian Rhythm Disturbance on the Human Musculoskeletal System and the Importance of Nutritional Strategies. Nutrients. 2023;15(3)

Why is in the world is this important to understand? Well, let’s now get into circadian biology and the musculoskeletal system.

Rogers N, Meng QJ. Tick tock, the cartilage clock. Osteoarthritis Cartilage. 2023

The CLOCK: BMAL1 circadian circuit regulates the musculoskeletal system (see figure above ⁴). In osseous structures, a synchronous circadian rhythm promotes healthy cartilage and bone formation. Individuals with a disrupted circadian rhythm, such as shift workers, have been shown to have pre-osteoporotic features such as reduced bone mass and density, altered bone microstructure, and decreased bone strength. Continuous light exposure can lead to bone loss and an increase in inflammatory cytokines, which can result in an increased risk of osteoporosis ². Epidemiological studies have found a correlation between shift work and a greater risk of hip and wrist fractures and knee osteoarthritis, suggesting that disrupted circadian rhythms could increase susceptibility to the degeneration of articular cartilage.

Research into the tendon circadian clock is still in the early stages. However, recent research on the tendon circadian clock has displayed a role in ectopic calcification, endoplasmic reticulum (ER) homeostasis, and type I collagen synthesis and secretion. There is a rhythmic oscillation of 4.6% of the genes in tendons. Also, about 10% of proteins in tendons undergo rhythmic oscillations. These clock-controlled outputs coordinate with the rest/activity cycle and contribute to maintaining a healthy balance of tendon tissues ⁵.

A recent study published in 2023 took biopsies from healthy patellar tendons and from individuals with chronic tendinopathy. Biopsies were taken at different times of the day to capture circadian variations. RNA sequencing, real-time quantitative polymerase-chain-reaction, and hydroxyproline assays were performed to analyze gene expression and collagen content. The study also involved tendon tissue culture using primary human tendon fibroblasts. Transmission electron microscopy was used to examine tendon ultrastructure, and fibril diameter measurements were completed using image analysis software. A total of 27 healthy individuals were recruited. Biopsies from 17 of these individuals were taken at 9am and 9pm for RNA and collagen measurement. Biopsies from the other 10 healthy subjects were taken at 4pm and 4am for electron microscopy. Ten patients with chronic patellar tendinopathy (>3 months) were also recruited. Biopsies were taken from the tendinopathic side and healthy side from 5 subjects at 9am and the other 5 subjects at 9pm and were used for RNA sequencing and real-time quantitative polymerase-chain-reaction analysis.  

The researchers detected 280 differentially expressed RNAs between the 2 time points with the majority being genes that code for proteins (see image below). They also observed upregulation of specific circadian clock genes during the day and others at night in the healthy tendon biopsies. Collagen related genes (COL1A1, COL1A2, and COL5A1) showed reduced expression during the night. However, in patients with chronic tendinopathy the circadian rhythm appeared to be disrupted. There was a loss of night-time reduction in the expression of Type I collagen fibrillogenesis genes in the tendinopathic patellar tendon. (Again, it is normal to have the reduction in collagen expression at nighttime). Interestingly, this reduction was also found in the patient’s contralateral tendon suggestive of altered homeostasis which may precede development of tendinopathy ⁶.

Yeung CC, Svensson RB, Yurchenko K, et al. Disruption of day-to-night changes in circadian gene expression with chronic tendinopathy. The Journal of physiology. 2023.

Skeletal muscle constitutes approximately 40% of total body weight and contains 50 to 75% of the body’s total proteins. Therefore, it consists of the largest collection of peripheral clocks in the human body. In a mouse study, the absence of BMAL1 expression led to muscle atrophy, reduced body weight, weak skeletal muscles, and structural muscle pathologies. Shift work circadian disruption has been shows to lead to a 23% decrease in insulin sensitivity. Disturbances in the muscle clock genes results in increased lipid oxidation and protein turnover which results in metabolic inefficiency ².

Juliana N, Azmi L, Effendy NM, et al. Effect of Circadian Rhythm Disturbance on the Human Musculoskeletal System and the Importance of Nutritional Strategies. Nutrients. 2023;15(3)

Notice we did not discuss anything about having an injury or some genetic predisposition you inherited from your mother. It is all about correct timing. Again, light is the strongest zeitgeber. Is this why you can be a couch potato, eating ice cream late into the night, watching TV and get osteoarthritis and tendinopathy without ever having injured your knee playing football?

I will let you decide….

1. Manoogian ENC, Panda S. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res Rev. 2017;39:59-67.
2. Juliana N, Azmi L, Effendy NM, et al. Effect of Circadian Rhythm Disturbance on the Human Musculoskeletal System and the Importance of Nutritional Strategies. Nutrients. 2023;15(3).
3. Rogers N, Meng QJ. Tick tock, the cartilage clock. Osteoarthritis Cartilage. 2023.
4. Yeung CC, Kadler KE. Importance of the circadian clock in tendon development. Curr Top Dev Biol. 2019;133:309-342.
5. Yeung CC, Svensson RB, Yurchenko K, et al. Disruption of day-to-night changes in circadian gene expression with chronic tendinopathy. The Journal of physiology. 2023.