The long-term objective of this research is to develop a non-invasive approach for assessment of de novo 3MH production in cancer patients early in the course of the disease as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on: 1) the known increase in de novo production of 3-methylhistidine (3MH) from muscle protein breakdown in said patients as a consequence of their unique disease-host interactions, and 2) earlier demonstration that de novo 3MH production can be measured in vivo using isotope dilution. We envision a relatively simple method that is totally non-invasive yet able to assess the course of skeletal muscle loss in cancer patients. The approach depends on the hypothesis that after an oral dose of deuterated 3-methylhistidine (D-3MH), the slope of the terminal portion of the decay curve (>12 hours post-dosing) for the tracer/tracee (D-3MH/3MH) in the free 3MH pool is directly proportional to the rate constant for myofibrillar protein degradation and can be determined from spot urine samples. During our Phase I research we established the feasibility of our overall approach by testing the following hypotheses in nine healthy adult males (four young, five older) by showing: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, (ii) meat intake up to and including the time of dosing does not influence the slope of the terminal portion of the isotope decay curve, and (iii) that the method is sufficiently sensitive to measure differences in the rate of 3MH production between young and older individuals. Testing the validity of these hypotheses was the central focus of the Phase-I research and crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. During Phase-II, we propose to conduct a statistically powerful prospective investigation to demonstrate that measurement of slope of the terminal decay curve (rate constant) with our approach in newly diagnosed cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to the manufacture and marketing of a suitable "Test Kit" for early identification of elevated muscle catabolism in at-risk patients so that medical intervention can take place and prevent future muscle atrophy.
Project Narrative Skeletal muscle loss is an important, but unpredictable, occurrence in many patients with different types of cancer and other chronic diseases. Early assessment is important because it would permit selection of high risk patients for preventive strategies. Once a clinically significant amount of skeletal muscle is lost in these patients it cannot be reversed and has poor prognostic implications. The purpose of this project is to develop a non-invasive method for early assessment of increased skeletal muscle degradation in non-small cell lung cancer patients. As a group, these patients have a high likelihood of weight- and skeletal muscle loss, but the results are expected to be applicable to other cancer types in which weight-loss is an important component. Our approach is based on development of a (non-radioactive) stable isotope tracer approach to permit accurate quantitative measurement of skeletal muscle degradation early in the course of the disease by monitoring spot urine samples for the ratio of labeled/unlabeled 3-methylhistidine the morning after consuming a small amount of labeled 3-methylhistidine along with a meat-free dinner.
|Sheffield-Moore, M; Dillon, E L; Randolph, K M et al. (2014) Isotopic decay of urinary or plasma 3-methylhistidine as a potential biomarker of pathologic skeletal muscle loss. J Cachexia Sarcopenia Muscle 5:19-25|