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Genetic Roles in Muscle Strength

Kostek, Matthew M.S.; Hubal, Monica J. Ph.D.; Pescatello, Linda S. Ph.D., FACSM

ACSM's Health & Fitness Journal: March-April 2007 - Volume 11 - Issue 2 - p 18-23
doi: 10.1249/01.FIT.0000262475.20949.bc

Learning Objective The primary learning objective for this article is to familiarize the health/fitness professional with basic genetic terminology and to review current knowledge about genetic contributions to human muscular strength.

This article reviews basic concepts in genetics and summarizes recent findings concerning associations between specific genes and human muscle strength.

Matthew Kostek, M.S., is a Ph.D. student at the Kinesiology Department of the University of Connecticut, where his research focuses on the physiological and genetic impact on physical fitness as well as genetic and behavioral contributions to exercise adoption and maintenance. He is ACSM Health/Fitness Instructor® certified.

Monica Hubal, Ph.D., is currently a postdoctoral fellow in the Research Center for Genetic Medicine at the Children's National Medical Center, where her research focuses on the underlying genetic and molecular mechanisms of skeletal muscle adaptation.

Linda Pescatello, Ph.D., FACSM, CPD, is a professor of Health Promotion and director of the Center for Health Promotion at the University of Connecticut. She holds joint appointments in the Departments of Kinesiology, Nutritional Sciences, and Physiology and Neurobiology at the University of Connecticut. Her research focuses on the physiological and genetic explanations of the health benefits of physical activity, particularly relating to hypertension.

Health/fitness professionals have likely heard the statement "It's all in the genes" to describe an elite athlete or even a healthy, trim individual. But what does this mean? Specifically, how do genes affect muscle strength? Can you, as a health/fitness professional, use genetic information to help your clients achieve optimal muscle performance? Scientists have begun to make significant progress in the ongoing quest to unravel the genetic basis for physical performance. This article provides a primer on genetics and reviews the current research concerning genetic contributions to human muscle strength.

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Genetics Primer

Genetics is a branch of biology that examines heredity and variation in organisms or simply the biologic traits that can be passed from parents to children. Genetics is the "nature" part of the "nature versus nurture" debate. The genetic material that lies in the nucleus of each human cell is composed of a DNA code; this code consists of tightly coiled nucleic acid strands arranged into genetic units called chromosomes. Genes, the basic unit of heredity, are made up of small molecules called nucleotides and are arranged along each chromosome (see Figure 1).

Figure 1

Figure 1

The human DNA code has approximately 3 billion pairs of nucleotides that comprise approximately 20,000 to 25,000 different genes (1), arranged on 23 pairs of chromosomes. Twenty-two chromosome pairs are called autosomes and are alike in men and women, whereas the 23rd pair (the sex chromosomes) differs between men (XY) and women (XX). Genes enable the body to produce many different proteins that serve different purposes throughout the body. For example, one gene could create a protein that influences eye color, whereas another protein could cause certain cells to grow hair. An observable physical attribute such as blue eyes or long hair is called a phenotype.

Each person shares an overwhelming percent of their genetic code (more than 99%) with other people. However, differences between people can be traced to small differences in the DNA code or differences in how the DNA code is read. Differences in the DNA code are called mutations. Mutations can be lethal, but most do not have a significant effect on the offspring's ability to survive and reproduce, and some can be beneficial. Thus, they can be passed on from generation to generation. It is these mutations that underlie the genetic diversity in human populations.



When humans are conceived, a genetic "shuffle" occurs, and people inherit approximately half their DNA code from their father and half from their mother. Because chromosomes are paired, each child will typically inherit two alleles (one from each parent for each gene), which occupy a given locus (position) on each chromosome pair. If a parent has a mutation in a given gene (i.e., a mutated allele), it has the possibility of being inherited by the offspring during the genetic shuffle.

The presence of a mutation in someone's DNA code can be determined by looking at his or her genotype, which is the combination of alleles for a given gene inherited from one's parents, which, along with the person's environment, influences a specific phenotype. In a typical gene, there are three possible genotypes: two homozygous genotypes, one consisting of two normal alleles (sometimes called wild type) and the other consisting of two mutant alleles (sometimes called variant type), and the heterozygous genotype, one normal allele and one allele with a mutation.

There are many different types of mutations, including insertions (extra nucleotides) and deletions (missing nucleotides). One common type of mutation is referred to as a single-nucleotide polymorphism (SNP, pronounced "snip") and is caused by a change in just one nucleotide of the DNA code. A variation must occur in at least 1% of the population to be considered a SNP. SNPs make up 90% of all human genetic variations and are a hot topic of current research.

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Mutations and Muscle Performance

Several genes have been identified with mutations believed to affect human muscle strength (2). Muscle strength is a complex trait because many factors contribute to what ultimately is expressed as muscle strength. For example, muscle strength varies according to muscle size (cross-sectional area), muscle fiber type, structure (i.e., arrangement and length of fibers), and neurological control (3). Muscle strength also can be measured in many different ways, including static, dynamic, or isokinetic assessments. Each of these components is likely influenced by different genes and their mutations. The estimated proportion of muscle strength that is inherited (i.e., caused by genetic influence) ranges from 30% to 95% in humans (4, 5). This range is large because genetic contributions to muscle strength likely differ depending on the contraction type, speed of contraction, and the specific muscle group tested. The rest of the variability in strength levels is caused by environmental factors, such as exercise training and other lifestyle behaviors.

Of the overall percentage of genetic variance in muscle strength measurement, it is common for a specific mutation to explain only a minute portion, such as 1% to 2%. In the realm of genetic studies involving muscle strength and SNPs, this is considered very significant because many do not find significant associations at all. It is likely that variations in several genes act together to influence larger portions of the genetic variance. Following is a brief summary of recent SNP associations with muscle strength.

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Genes Associated With Muscle Strength

Myostatin (growth differentiation factor 8) is a growth factor that inhibits muscle tissue growth (i.e., higher activity of the myostatin pathway in the body causes an individual to have smaller muscles). Specifically, the myostatin pathway activity limits the number of muscle fibers produced in a developing fetus and inhibits the development of muscle precursor cells (also known as satellite cells) in adults, resulting in smaller muscles. A myostatin mutation found in some cattle produces a "double-muscling" effect, where muscle mass is significantly higher than normal cattle (6). A recent case report (7) demonstrated dramatically increased muscle size in an infant with a mutation in the myostatin gene. These findings are particularly important because they may eventually lead to effective treatments for muscle wasting diseases in humans such as muscular dystrophy and sarcopenia.

Insulin-like growth factor 1 (IGF-1) is a protein well known to play key roles in muscle size, function, and adaptation (for review, see Ref. 8). Several mutations in the IGF-1 gene have been identified that can affect IGF-1 protein levels. In recent research, investigators found a significant association between IGF-1 genotype and increases in dynamic strength (assessed via the one repetition maximum testing) in 67 older adult men and women after 10 weeks of single-leg knee extension training. These findings, if validated in additional studies with larger sample sizes, may lead to effective therapeutic treatments to increase muscle strength in frail populations.

A mutation in a similar gene, IGF-2, also has been shown to be associated with muscle strength and power in two separate samples from the Baltimore Longitudinal Study of Aging (10). IGF-2 is a growth factor involved in growth and regulation of skeletal muscle. One study examined 94 men who were tested for strength and power using an isometric handgrip dynamometer during a period of 25 years. The second study assessed isometric arm and leg strength in 485 men and women at regular intervals during a period of 10 years. These studies (10) found that strength and power were greater across the adult lifespan for a particular IGF-2 genotype, suggesting that IGF-2 associates with strength and power in men and women. They concluded that variation within this gene that affects muscle development may influence muscle strength later in life.

α-Actinin 3 (ACTN-3) is a muscle protein found specifically in Type II (i.e., fast-twitch) muscle fibers. Approximately 18% of the population has a SNP that causes two copies of the mutated allele to produce no ACTN-3 protein. Indirect evidence had previously associated ACTN-3 to muscle performance based on several population studies of different athlete cohorts (i.e., sprinters vs. endurance athletes). To directly investigate associations between ACTN-3 genotype and muscle strength, Priscilla M. Clarkson, Ph.D., FACSM, and colleagues (11) tested 602 adult men and women after a 12-week single-arm resistance training program. Isometric and dynamic elbow flexor strengths were measured before and after the 12-week training period. No association between ACTN-3 and muscle strength was found in men; however, variation in ACTN-3 genotype was associated with variation in muscle strength in women. Although these data suggest a link between ACTN-3 genotype and muscle function in women, more investigations are needed to fully explore the consequences of ACTN-3 deficiency.

Angiotensin-converting enzyme (ACE) is an enzyme that is involved in vascular function. The ACE insertion/deletion polymorphism (ACE I/D) has three genotypes, the insertion allele differs from the deletion allele in that it includes an extra series of nucleotides and is associated with lower amounts of circulating ACE. ACE I/D has been widely studied in a variety of athletes (12-14) and is linked to endurance capacity, response to endurance training, and muscle strength (15). In a recent study, Linda S. Pescatello, Ph.D., FACSM, and colleagues (16), using the same design as Dr. Clarkson and colleagues (11), examined 631 men and women for associations among ACE I/D and muscle strength. After 12 weeks of unilateral resistance training of the nondominant arm, these investigators found that the ACE I/D associated with neurological signaling to muscle, as the ACE I/D genotype was associated with strength increases in both the trained and untrained arms. This suggests that ACE I/D genotype is involved in neural learning during strength training (16). This is a new finding and brings about some important questions on the role of ACE I/D in muscle performance. More research is needed to determine the role of ACE I/D in muscle performance.

Despite the importance of muscular strength to the individual's execution of activities of daily living throughout the life span, research on genetic contributions to muscle strength has only recently grown. The number of published research articles exploring genetic contribution to muscle strength increased gradually from two in 2000 to 16 in 2005; the number of candidate genes studied in scientific journals for muscle strength and power also increased from two in 2000 to 13 in 2004 (17). Although the studies mentioned previously found genetic links to muscle strength, other studies involving the same mutations did not. Thus, until more research is done to substantiate those findings, as compelling as they are, they should be taken with a measure of skepticism.

To summarize:

  • Myostatin (growth differentiation factor 8) inhibits muscle growth. Certain myostatin mutations influence muscle size in cattle. Recent evidence suggests that these mutations may influence muscle strength and size, which may be potentially beneficial for the treatment of muscle wasting diseases in the future.
  • IGF-1 is involved in muscle growth and development. The IGF-1 genotype is associated with increases in dynamic muscle strength. Sarcopenia and muscle weakness may eventually be targets of IGF-1-based therapies.
  • IGF-2 is involved in muscle growth and regulation. The IGF-2 genotype is associated with greater muscle strength and power across the life span and may have potential implications in sustained quality of life in the elderly.
  • ACTN-3 is a muscle fiber protein found specifically in Type II muscle fibers. Variation in ACTN-3 genotype contributes to variation in muscle performance in women.
  • The ACE I/D is involved in vascular function. Studied widely in endurance and national-level athletes, new evidence shows that ACE I/D may be involved in the cross-education effects of strength training.
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Implications for Health/Fitness Professionals

Health/fitness professionals are apt to face future challenges in how to optimize exercise training for individuals with desirable strength/exercise genes, as well as for motivating individuals without desirable strength genes to begin and/or continue exercising. To meet these challenges, health/fitness professionals will need to become familiar with exercise genomics (i.e., studying how genetic and environmental factors affect exercise performance) and how it affects muscle strength as well as other exercise-related phenotypes such as aerobic capacity.

Another area of important genetic research that has implications for fitness professionals arises from the expansion of nondisease genetic testing. Genetic testing for nondisease traits such as muscle strength will likely become common in the next decade (18). New technologies make genetic testing cheaper and more available to the public. There are currently several companies that offer genetic testing regarding lifestyle and physical performance (18). Fitness professionals will likely be asked by individuals who choose to have themselves tested for particular genes about the impact those results have on their training. However, the positive and negative implications for genetic screening for nondisease phenotypes are still unknown (see sidebar).

Certifying bodies in sports medicine, such as the American College of Sports Medicine, will need to create forums for discussion about genetic testing, the potential dangers and benefits of genetic knowledge, and how individuals with and/or without perceived desirable genes can be accommodated. Courses in basic exercise genomics and ethics will need to be offered in health/fitness curricula if they aren't already. In addition, professionals will need to agree on standards, that is, position stands on how genetic knowledge for exercise performance can be used safely and ethically in the population.

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Muscle strength is a multifactorial trait that varies in humans. Genetics accounts for a significant part of this variance. Mutations in specific genes account for a small portion of the genetic variance, and their effects on exercise traits are just beginning to be understood. More research is needed to substantiate current significant findings. With new technologies developing, genetic testing is likely to become increasingly available to the public. Exercise professionals will need to prepare themselves for the emerging challenge of optimizing training based on genetic information and meeting the needs of individuals with genetic self-knowledge.

For further information on exercise genomics, interested readers can explore the following sources:

  • Bouchard C., R. Malina, L. Pérusse. Genetics of Fitness and Physical Performance. Champaign, IL: Human Kinetics, 1997. This compendium authored by Claude Bouchard, Ph.D., FACSM, Robert Malina, Ph.D., FACSM, and Louis Pérusse, Ph.D., summarizes early research on human genetics and physical performance as well as methods used in human genetic research.
  • This is the HERITAGE family study Web site. The main objective of this linkage study is to examine the role of genotype in the response to aerobic exercise training as well as effects of regular exercise on cardiovascular risk factors.
  • Rankinen, T., M.S. Bray, J.M. Hagberg, et al. The human gene map for performance and health-related fitness phenotypes: the 2005 update. Medicine & Science in Sports & Exercise® 38(11):1863-1888, 2006. Reviews and summarizes current research on health and physical performance phenotypes.


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Glossary of Genetic Terms:

Allele: Different versions of the same gene inherited from each parent. An allele occupies a given locus (position) on a specific chromosome.

Chromosome: Tightly coiled strands of genes found in the nucleus of every cell.

DNA: Molecule found in the nucleus of a cell consisting of nucleotides and shaped like a double helix.

Exercise genomics: The study of the molecular mechanisms and interplay of genetic and environmental factors in exercise performance.

Gene: The basic unit of heredity that determines a particular characteristic in an organism.

Genetics: The branch of biology that examines heredity and variation of organisms.

Genotype: The combination of alleles for a certain gene that, along with the environment, influences a specific phenotype.

Heterozygous: Having two different alleles for a given gene.

Homozygous: Having identical alleles for a given gene.

Mutation: A heritable change in the DNA sequence.

Phenotype: An observable attribute of an organism.

Single-nucleotide polymorphism (SNP): A change in just one nucleotide of the DNA code that is present in more than 1% of the population.

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The authors thank Dr. Clarkson, School of Public Health and Health Sciences, University of Massachusetts, Erynn Gordon, M.S., certified genetic counselor, and Dr. Devaney, research scientist at the Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, for their help in editing this manuscript.

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Condensed Version and Bottom Line

Muscle strength is a complex trait that varies widely among humans. A significant portion of this variation is likely influenced by multiple genes, and researchers are continually updating what is known about genetic influences on muscle performance. Optimizing exercise training programs for individuals based on genetic knowledge will pose a challenge for health/fitness professionals. To meet this challenge, health/fitness professionals will need to become familiar with the basics of exercise genetics and how muscle strength, as well as other related exercise and physical performance characteristics, can be affected by an individual's genetic background.

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    Gene; Polymorphism; Hypertrophy; Self-Concept; Strength Training

    © 2007 American College of Sports Medicine