Deficiency for interleukin 15 receptor produces super-athletic mice
Several diseases – and just plain old getting old – are associated with reduced stamina and/or muscle function. If what was recently discovered in mice can be applied to people, there may be a way to enhance muscle performance and retrieve some of that lost vigor. A group of American and Australian researchers led by Dr. Tejvir S. Khurana from the Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania, Philadelphia, has found that mice deficient for the interleukin 15 receptor have considerably more endurance than their wild-type counterparts (Pistilli et al. 2011). The team's findings may lead to therapies that increase muscle performance in people in athletes and people with muscle diseases and metabolic and/or age-related disorders.
Interleukin 15 and its receptor
Interleukin 15 (IL15) and a component of its trimeric receptor, interleukin 15 receptor alpha (IL15Ralpha), are widely expressed throughout the body, including in muscle. Although they are usually associated with the immune system, they have other functions. In mice, the two molecules have numerous neurological and locomotor roles. In humans, IL15 SNPs are associated with muscle phenotypes, muscle responses to resistance training, metabolic syndrome and obesity.
Fast muscles of Il15ra-deficient mice act like slow muscles
Based on the reported muscle functions of IL15 and IL15Ralpha, the Khurana team hypothesized that IL15R alpha helps define the phenotype of fast skeletal muscle. To test their hypothesis, they compared the fast and slow muscles among groups of males from three strains of genetically modified mice and four controls: an Il15ra knockout (KO) strain, B6;129X1-Il15ratm1Ama/J (003723), and control strains B6129SF2/J (B6129, 101045) and C57BL/6J (B6J, 000664), from The Jackson Laboratory; an Il15 KO strain and control BL/6NTac, both from Taconic; and an Il15 over-expressing transgenic strain, HSA-IL15TG, and control strain HSAIL-15Con, both produced by Quinn et al. (2009). The fast muscle examined was usually the extensor digitorum longus, occasionally the tibialis anterior, and the slow muscle was the soleus. Their findings are summarized below:
- Il15ra KO fast muscle is significantly more fatigue-resistant than either Il15 KO or HSA-IL15TG fast muscle.
- Although the wet weight and whole muscle cross-sectional area of Il15ra KO fast muscle are comparable to those of B6129 controls, their contractile phenotypes are more like those of slow muscles (generate low isometric forces and exhibit a low twitch/tetanus ratio). The fibers are smaller but more numerous, have proportionately more nuclei per fiber, and have more centrally located nuclei per fiber than do normal fast muscles.
- The contractile phenotypes of slow muscles from Il15ra KO mice and of both slow and fast muscles from Il15 KO and HSA-IL 15TG mice are comparable to those of their respective controls, indicating that IL15R alpha does not play a role in defining slow muscle phenotypes, and that IL15 does not play a role in defining either slow or fast muscle phenotypes.
- Il15ra KO mice are more active at night and during the day and, during the same amount of time, run over six times farther than B6129 controls (they also run farther than B6J controls).
- Il15ra KO fast muscle fibers exhibit changes consistent with altered calcium homeostasis and have significantly more markers of mitochondrial biogenesis per fiber than B6129 fast muscle fibers.
- SNP rs2228059 in the human IL15RA gene is associated with better performance among elite/Olympic-level athletes in certain endurance sports.
In summary, the Khurana team produced compelling physiological and molecular evidence that IL15R alpha has the previously unknown function of defining the contractile and morphological phenotypes of fast skeletal muscle. Typically, fatigue resistance is characteristic of slow skeletal muscles, such as the soleus, and is due to a combination of many mitochondria, low glycolytic oxidative enzyme capacity, high capillarity, and small muscle fibers. In contrast, due to fewer mitochondria, high glycolytic enzyme capacity, low capillarity and large muscle fibers, fast muscle usually fatigues quickly. The team found that the fast muscles of Il15ra KO mice are more characteristic of slow muscles. The fact that the Il15 KO mice and the Il15 over-expressing transgenic mice exhibit neither similarly nor oppositely altered phenotypes indicates that the muscle-related functions of the IL15 receptor and those of the IL15 gene are distinct. The findings by the Khurana team may lead to novel therapies for improving muscle performance in a variety of muscle- and age-related diseases and metabolic disorders.