Understanding Muscle Protein Dynamics: Technical Considerations for Advancing Sarcopenia Research

Abstract

Sarcopenia, the age-related degenerative loss of muscle mass and function, is considered a muscle disease (i.e., muscle failure) 1) and is central to functional and metabolic alterations in various clinical conditions such as critical illness (e.g., burn injury and cancer), chronic diseases (e.g., heart failure), insulin resistance, obesity, and osteoporosis. 2) Therefore, discovering effective therapeutic means to counteract sarcopenia progression is of utmost importance to improve the quality of life in older adults and is a major target for drug development; however, efforts have not yet led to clinically meaningful success. 3) The etiology of sarcopenia is multifactorial, including alterations in hormones and sex steroids, physical inactivity, and comorbidities. 4) It is, therefore, difficult to understand the underlying mechanism(s) at molecular Sarcopenia, which is the loss of muscle mass and strength that occurs with aging, involves imbalanced muscle protein turnover (i.e., protein breakdown exceeding synthesis), which in turn exacerbates other clinical conditions such as type 2 diabetes mellitus, obesity, osteoporosis, and cancer, thereby worsening the quality of life in older adults. This imbalance is attributed in part to the resistance of aged muscle to anabolic stimuli such as dietary protein/amino acids and resistance exercise known as anabolic resistance. Despite research efforts, no practical therapeutics have been successfully discovered possibly because of a lack of understanding of the dynamic nature of muscle protein, and the use of indirect assessments of muscle mass. Herein, we briefly discuss the regulation of protein turnover in response to the abovementioned anabolic stimuli with respect to anabolic resistance and optimal protein intake, followed by methodological considerations for advancing sarcopenia research, including assessments of muscle mass and dynamics.

In Vivo and In Vitro Quantification of Glucose Kinetics: From Bedside to Bench

“…Dynamic information on the metabolic status of substrates including glucose, lipids, amino acids/proteins in organisms (i.e., metabolic flux or kinetics) in vivo and in vitro can be best explored with the introduction of one or more of molecules that are labeled with either a stable or radioactive isotope (i.e., metabolic tracer) into the circulation in the body [ 11 , 15 , 16 , 26 – 28 ]. Here our emphasis will be placed on the applications of stable isotope tracer methodology owing mainly to (1) safety issues, particularly for humans and (2) the versatility of stable isotope tracers in assessing various aspects of metabolism [ 7 , 15 , 16 , 29 – 35 ].…”

“…In other words, the faster the tracee turnover, the lower the E p for a given F . The tracer dilution model can be applicable to assessments of in vivo kinetics of various metabolites including amino acids [ 26 , 44 – 46 ], palmitate [ 6 , 47 , 48 ], glycerol [ 49 – 51 ], pyruvate [ 52 ], lactate [ 53 – 55 ] as well as glucose [ 8 , 11 , 56 , 57 ] in steady states and non-steady states.…”

Sarcopenia and Muscle Aging: A Brief Overview

“…However, when muscle becomes resistant to these stimuli this is termed anabolic resistance (AR). AR is a phenomenon defined by the diminished ability to increase the rate of protein synthesis and adapt to anabolic stimulation [ 17 , 18 ]. AR is often observed in aged muscle and is probably a crucial driver of sarcopenia and physical frailty [ 19 , 20 ].…”

“…AR, as described above, is defined by a diminished muscle protein synthetic rate following anabolic stimulation such as amino acids, muscle contraction, or anabolic hormones and is often observed with aging [ 17 , 18 , 20 , 97 , 98 ]. Thus theoretically, overcoming AR by supplementing with anabolic stimulants like essential amino acids (EAA) and resistance exercise are recommended avenues to combat sarcopenia [ 99 , 100 ].…”

“…These findings indicate that sarcopenia could be composed of several subclasses of diseases originated by distinct internal (intramuscular) or external (systemic) triggers. To overcome AR and to develop novel therapeutics for sarcopenia, multi-omics analyses including not only genome, transcriptome and proteome but also metabolome and floxome (complete set of metabolic fluxes) have to be explored [ 18 , 103 ].…”