3-Methylhistidine

3-Methylhistidine (3-MH), a derivative of the essential amino acid histidine, is primarily found in skeletal muscle proteins. 

While histidine itself plays various roles in the body, including acting as a precursor to histamine and buffering pH levels, 3-MH does not have direct physiological functions. Instead, it serves as a crucial biomarker for muscle metabolism and catabolism, indicating muscle protein breakdown. 

Elevated 3-MH levels can suggest increased muscle turnover due to factors like strenuous exercise, muscle injury, or metabolic disorders.

Dietary intake, particularly of poultry and fish, significantly influences 3-MH levels, making it a useful marker for meat consumption. 

Testing for 3-MH in urine or plasma is essential in nutritional studies and clinical settings to assess muscle health and dietary habits. 

Elevated 3-MH levels can also reflect higher lean muscle mass and better nutritional status, while low levels may indicate muscle wasting or inadequate protein intake.

Understanding 3-Methylhistidine

Definition and Overview of 3-Methylhistidine  [2., 5., 8., 10.] 

3-Methylhistidine is a derivative of histidine.  Histidine is an essential amino acid found abundantly in skeletal muscle proteins. 

Histidine itself plays multiple roles in the body, including acting as a precursor to histamine, contributing to the buffering of pH levels, and facilitating metal ion chelation. 

Histidine may be methylated in two different locations, forming either 1-methylhistidine (1-MH) or 3-methylhistidine (3-MH).  Either can be formed by adding a methyl group to histidine residues in myosin and actin, the major proteins in muscle tissue. 

Unlike histidine, both 1-MH and 3-MH do not have physiological roles in the body.  However, both 1-MH and 3-MH can provide clinically useful information.   

1-Methylhistidine vs. 3-Methylhistidine

In studies examining the impact of diet on muscle metabolism, two key biomarkers, 1-methylhistidine (1-MH) and 3-methylhistidine (3-MH), have shown distinct patterns.  [8.]

3-MH levels are predominantly derived from endogenous sources related to muscle metabolism in humans, making 3-MH an appropriate marker for human muscle catabolism.  

3-MH is formed from the methylation of histidine in muscle proteins such as actin and myosin, indicating it is more closely related to muscle metabolism and turnover. Elevated levels of 3-MH can suggest increased muscle breakdown, making it relevant in studies of muscle physiology or conditions affecting muscle integrity.

Skeletal muscle, which constitutes a major portion of body mass, releases various metabolites into biofluids when it undergoes stress or damage. 

For instance, drugs like cerivastatin have been observed to cause skeletal muscle necrosis in animal models, notably increasing the levels of 3-methylhistidine in urine and serum.  [15.]

In contrast, 1-MH is not made in human tissues but it is formed in animal muscle tissues.  1-MH primarily originates from the dietary intake of anserine.  

Due to its abundance in certain muscle-related proteins and particularly high levels of anserine found in poultry and fish, 3-methylhistidine is a useful biomarker for meat consumption. Dietary studies indicate that general poultry consumption (p-trend = 0.0006) and specifically chicken consumption (p-trend = 0.0003) are linked to increased 3MH levels in human plasma.  [11.] 

Fish consumption, especially salmon and cod, also raises 3MH levels in serum and urine.  [4.] 

Typically, urinary 3MH is associated with white meat intake (p<0.001), while urinary 1-methylhistidine (1MH) is linked to red meat intake (p<0.001).  [6.] 

However, it is generally understood that 1-MH is a useful biomarker for monitoring meat consumption, as it reflects dietary intake rather than endogenous metabolic activity.  [7., 8.]

Laboratory Testing for 3-Methylhistidine

Overview of Laboratory Methods

Testing for 3-MH typically involves urine or plasma analyses. 

Assessing the levels of 3-MH can be important in nutritional studies or in clinical settings where understanding a person's meat consumption is relevant to their health or dietary habits.  

Sample Collection and Preparation

Urine samples may be collected at home or in a clinical setting.  

Blood samples may also be collected, typically via venipuncture.

Consult the ordering provider to determine if any test preparation, such as fasting, is required.

Interpretation of Test Results

Optimal Level for 3-Methylhistidine

Generally, optimal levels for 3-methylhistidine fall within the recommended reference ranges, although values toward the upper end of the range typically are considered optimal.  [1.]

It is important to consult the reference ranges provided by the laboratory company used.  The following reference ranges have been recommended by various laboratory companies:

Urine 3-MH, Adult: 55-110 microMol/g creatinine [16.] 

Plasma 3-MH, Adult: 2-9 μmol/L [14.] 

Clinical Significance of Elevated 3-Methylhistidine Levels 

Elevated 3-MH levels are indicative of increased skeletal muscle protein breakdown or catabolism. This can occur due to muscle injury, strenuous exercise, fasting, or certain metabolic disorders.  [10.]

It may also be associated with higher lean muscle mass.  In patients with chronic kidney disease, particularly those on hemodialysis, elevated 3-MH levels have been associated with better nutritional status and higher lean tissue mass.  [1.] 

3-methylhistidine has also been considered as a predictor of cardiovascular events and mortality.  Paradoxically, low serum 3-MH levels in hemodialysis patients have been linked to an increased risk of cardiovascular events and mortality.  [1,] 

Elevated 3-MH levels can also result from the consumption of meat, fish, and soy-based products, which contain 3-MH or its precursors.  [6.] 

Clinical Significance of Low 3-Methylhistidine Levels

Low levels of 3-methylhistidine (3-MH) in urine or blood can have clinical significance, as they may indicate certain conditions or nutritional states. 

Low 3-MH may indicate low muscle mass or muscle wasting.  Since 3-MH is a byproduct of muscle protein breakdown, low levels may suggest reduced skeletal muscle mass or muscle wasting conditions.  [12.] 

Low 3-MH levels can also indicate low dietary intake of proteins, particularly from animal sources like meat and fish. 

Low 3-MH levels should be interpreted in conjunction with other markers of muscle mass, protein intake, and nutritional status for a comprehensive assessment of metabolism and mitochondrial function.  

If these deficiencies appear elsewhere in the test results, it indicates that although protein is being metabolized, the Krebs cycle is functioning at a slower rate than normal. This can be associated with symptoms such as fatigue and low body temperature.  [9.] 

Testing Biomarkers Related to 3-Methylhistidine

Other biomarkers are associated with muscle metabolism and nutritional status, complementing the assessment of 3-Methylhistidine levels.

Creatinine

Creatinine is a waste product generated from the breakdown of creatine phosphate in muscle tissue.  It is excreted through the kidneys and serves as a marker of muscle mass and renal function.  

Creatinine levels are commonly measured in urine and blood samples, with elevated levels indicating increased muscle breakdown or impaired kidney function. 

Urinary Nitrogen

Urinary nitrogen is derived from the breakdown of dietary protein and endogenous protein turnover.  Measurement of urinary nitrogen levels allows for the estimation of protein intake and utilization, reflecting overall protein balance in the body. 

Elevated urinary nitrogen excretion may indicate increased protein catabolism, while decreased excretion may suggest inadequate protein intake or impaired protein synthesis. 

Assessing urinary nitrogen levels in conjunction with 3-Methylhistidine may provide insights into muscle protein turnover and nutritional adequacy.

Serum Albumin

Serum albumin is a major protein synthesized in the liver and serves as a marker of nutritional status and inflammation. Decreased serum albumin levels are associated with malnutrition, chronic diseases, and increased risk of morbidity and mortality.  [3.] 

Monitoring serum albumin levels alongside 3-Methylhistidine helps assess protein status and nutritional adequacy, guiding interventions to optimize muscle health and overall well-being.

Branched-Chain Amino Acids (BCAAs)

Branched-chain amino acids including leucine, isoleucine, and valine, are essential amino acids involved in muscle protein synthesis and energy metabolism. Alterations in BCAA levels may indicate changes in muscle protein turnover, nutritional status, or metabolic dysfunction. 

Measuring BCAA concentrations alongside 1-Methylhistidine provides additional insights into muscle metabolism and nutritional status, facilitating targeted interventions to support muscle health and function.

Increasingly, laboratory companies offer specialized testing to assess levels of various amino acids, including 1-methylhistidine, 3-methylhistidine, and BCAAs, in urine and blood.  Some examples of these tests include:

Plasma Amino Acid Tests:

Amino Acids Analysis by Genova Diagnostics

Amino Acids Plasma Test by Mosaic Diagnostics

Plasma Amino Acids Analysis by Diagnostic Solutions Laboratory

Urine Amino Acid Tests:

Urine Amino Acids Test: 24 Hour by Doctor’s Data

‍Urine Amino Acids Test: First Morning Void by Doctor’s Data

‍Amino Acids Urine Test: 24 Hour or Random by Mosaic Diagnostics

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