1-Methylhistidine

1-Methylhistidine is a derivative of the amino acid histidine, found in foods and synthesized from the dipeptide anserine in the body. 

Unlike histidine, which participates in various biochemical functions such as proton buffering and metal ion chelation, 1-methylhistidine is primarily a biomarker for dietary meat intake, as it is not synthesized in humans but results from meat consumption. 

It reflects the metabolic processing of specific histidine-containing proteins from dietary sources and has no reported major physiological roles in human metabolism.

This article examines the properties and functions of 1-methylhistidine, as well as describing its utility in clinical assessment via lab testing to assess muscle and nutrition status.

Understanding 1-Methylhistidine

Definition and Overview of 1-Methylhistidine  [4.]

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

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. 

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. 

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.   

While 1-MH lacks the biochemical roles of histidine, it is useful as a biomarker for dietary meat intake, as it is found in significant amounts in meat products and is a breakdown product of the dipeptide anserine, which is present in muscle tissue.

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.  [2.]

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.  [8.]

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, a dipeptide abundant in meats like chicken. This makes 1-MH a useful biomarker for monitoring meat consumption, as it reflects dietary intake rather than endogenous metabolic activity.  [2., 5.]

Metabolism of 1-Methylhistidine

The primary source of 1-MH in the human body is from the consumption of foods rich in anserine, particularly meat and fish. Once ingested, anserine is broken down into 1-MH and other byproducts; thus, the presence of 1-MH in the body is reflective of meat consumption. 

Once synthesized, 1-methylhistidine is released into the bloodstream and subsequently excreted primarily through the kidneys. Its half-life clearance has been reported at 11.7 hours.  [6.]

1-Methylhistidine Excretion in Vegetarians vs. Omnivores  [6.]

The metabolism and excretion of 1-methylhistidine (1-MH) in humans show significant variation based on diet, particularly meat consumption. Omnivores typically exhibit higher urinary levels of 1-MH compared to vegetarians. 

This pattern was evident across different demographic groups, showing statistically significant differences in 1-MH excretion between omnivores and vegetarians. Higher meat intake, especially poultry and red meat, correlates with increased excretion of 1-MH. 

This relationship is utilized to validate dietary intake assessments, confirming that urinary 1-MH can serve as a reliable indicator of meat consumption in dietary studies.

Furthermore, the excretion of 1-MH does not increase with muscle catabolism or trauma, distinguishing it from 3-methylhistidine, which is influenced by muscle mass and dietary intake. 

Therefore, 1-MH serves as a more specific marker for meat consumption compared to other metabolites. The findings support the use of urinary 1-MH levels in epidemiological studies to assess meat intake and validate vegetarian status, providing a useful tool for dietary research and potential implications for disease risk assessments.  [6.] 

Laboratory Testing for 1-Methylhistidine

Overview of Laboratory Methods

Testing for 1-MH typically involves urine or plasma analyses. 

Assessing the levels of 1-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,2 is required.

Interpretation of Test Results

Reference Ranges for 1-Methylhistidine

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

Urine 1-MH, Adult: 23-1339 nmol/mg creatinine [1.] 

Plasma 1-MH, Adult: ≤47 μmol/L [7.] 

Clinical Significance of High 1-Methylhistidine

Elevated 1-MH levels typically indicate increased intake of meats, such as chicken, which are rich in anserine—a dipeptide that breaks down into 1-MH upon digestion. 

In medical research, measuring 1-MH can be crucial for studies assessing the impact of diet on health, including conditions influenced by dietary habits like cardiovascular diseases or metabolic disorders. 

Furthermore, since 1-MH is not significantly influenced by endogenous muscle activity, its levels can provide a clear and direct insight into dietary protein sources without the confounding effects seen with other metabolites related to muscle metabolism.

Clinical Significance of Low 1-Methylhistidine

Low levels of 1-methylhistidine (1-MH) in urine or blood primarily indicate a reduction in meat consumption, as 1-MH is a metabolite predominantly derived from the dietary intake of meat, particularly from meats rich in anserine such as chicken and fish. 

Clinically, monitoring 1-MH can be useful for validating adherence to dietary recommendations in patients undergoing nutritional therapy for various health conditions, including kidney disease, where protein intake often needs to be controlled. 

Additionally, low 1-MH levels could be useful in studies examining the effects of vegetarian or low-protein diets on health outcomes, providing a biochemical marker to assess dietary compliance and its impact on muscle metabolism and overall health.

Testing Biomarkers Related to 1-Methylhistidine

Other biomarkers are associated with muscle metabolism and nutritional status, complementing the assessment of 1-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 1-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.  [GIBBS>>>>>>> 

Monitoring serum albumin levels alongside 1-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

Clinical Applications of 1-Methylhistidine Testing

Diagnosis and Monitoring of Muscle Disorders

1-Methylhistidine testing may play a crucial role in distinguishing muscle disorders, such as muscular dystrophy, myopathies, and sarcopenia, from increased dietary intake of animal protein.  This is best assessed in conjunction with testing levels of 3-methylhistidine to distinguish dietary protein intake from increased muscle turnover.  

Assessment of Nutritional Status

Assessing 1-Methylhistidine levels provides valuable insights into nutritional status and protein metabolism. Decreased 1-Methylhistidine levels may indicate inadequate protein intake or impaired protein synthesis, highlighting nutritional deficiencies or malnutrition. 

Conversely, elevated 1-Methylhistidine levels may reflect increased animal protein intake, which can provide insight into nutritional assessments.

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