An international research team studying why some weightlifters’ muscles grow much more quickly than others’ has identified a set of 141 genes that appear to regulate growth of the body’s skeletal muscles. Headed by scientists at McMaster University, the investigators, who are based in Canada, the United States, and the U.K., carried out a novel experiment in which volunteers worked out one leg and immobilized the other. The results showed that after just two weeks, the immobilized leg lost, on average, the same amount of muscle mass as the opposite leg had gained through more than two months of weight training.

Comparing the genetic responses of the muscles in the two legs of the same individual helped the team to more precisely isolate what drives exercise-related muscle growth, and has provided new insights that could ultimately help to develop new strategies against debilitating muscle loss in older people.

“Building and retaining muscle is critical to overall health and quality of life,” said Tanner Stokes, a kinesiology PhD student and lead author of the research, which was published in Cell Reports. “If we can target those genes with lifestyle and drug therapies, we may be able to help seniors and others vulnerable to muscle loss.”

Stokes and colleagues report their findings in a paper titled, “Molecular Transducers of Human Skeletal Muscle Remodeling Under Different Loading States.”

Exercise such as weight lifting is a form of skeletal muscle loading that stresses the muscles and results in muscle fiber hypertrophy, which effectively builds muscle. Conversely, muscles that aren’t used weaken, and muscle fiber atrophy results. However, the degree by which muscles will strengthen or weaken in response to loading or unloading (UL) varies greatly between individuals, and this can make it hard to identify how the underlying processes are regulated at the molecular level. “In humans, voluntary loading (via resistance exercise training [RT]) leads to a highly heterogeneous physiological adaptation across individuals, which is associated with differential molecular response,” the authors wrote. “The key regulators of heterogeneous muscle remodeling in response to loading and UL are unknown.”

Researchers are interested in finding out the basis of these differential responses because they could impact on frailty in older people. “Many variables influence muscle responses to loading—age, biological sex, diet, and genetic variation,” the researchers continued. “The implications of this heterogeneity are substantial, influencing muscle insulin sensitivity and age-related musculoskeletal frailty and potentially underpinning the compromised in older individuals.”

To take inter-individual variation in molecular responses out of the equation, Stokes and colleagues devised an experiment in which muscle loading and unloading could be studied in the same individual, by exercising only one leg, and immobilizing the other, making it possible to look for genetic changes associated with those processes. This experimental model is known as HypAt. As the authors explained, “We contrasted muscle subjected to a loading hypertrophic stimulus with the paired (contralateral) muscle subjected to UL to induce atrophy (a model called HypAt). The aim of the HypAt model is to measure molecular responses to loading and UL within an individual to reduce heterogeneity and more readily reveal potential regulators.”

The experiment was carried out in a group of young volunteer men, over 10 weeks. Throughout the study, the participants undertook a prescribed regime of weight training to built up muscle in one of their legs. For the first eight weeks of the study, the opposite leg served as a non-exercising control. For the last two weeks, the non-exercising leg was immobilized entirely with a brace to keep it from bearing weight. “The variation in muscle growth between people makes it very challenging to isolate what drives that growth,” said Stokes. “Using both legs of the same person to both load and unload muscles allowed us to make a direct comparison.”

The team found that the variation in muscle gain through weightlifting was consistent with results that the project’s supervisor, Stuart Phillips, PhD, a professor of kinesiology, had seen in 22 years of studying muscles at McMaster. The results showed that muscle gains in the subjects’ active legs ranged from 1–15% across the full 10 weeks, and averaged 8%. In contrast, muscle loss in their immobilized legs ranged between 1% and 18%, averaging at 9%. In other words, the average subject lost muscle through inactivity at about five times the rate he had gained it through weightlifting.

Interestingly, the team discovered a core of 141 genes that correlated with muscle growth, and they validated their findings in independent samples. Laboratory tests in muscle cells further showed that some of the genes were regulators of protein synthesis. The findings indicated that regulated genes form functional networks central to muscle plasticity, with several network genes directly regulating muscle cell protein synthesis.

“Implementing a within-person loading and analysis strategy facilitated the identification of the genome-wide molecular analysis of human muscle remodeling in a small human cohort,” the team concluded. “A subset of transcripts was found to be regulated in proportion to the magnitude of human muscle growth, including members of validated growth and atrophy canonical pathways … Using proteome-constrained networks and pathway analysis reveals notable relationships with the molecular characteristics of human muscle aging and insulin sensitivity, as well as potential drug therapies.”

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