Date Published: February 7, 2017
Publisher: Public Library of Science
Author(s): Omar Cortez-Toledo, Caitlin Schnair, Peer Sangngern, Daniel Metzger, Lily C. Chao, Rebecca Berdeaux.
Muscle atrophy is a prevalent condition in illness and aging. Identifying novel pathways that control muscle mass may lead to therapeutic advancement. We previously identified Nur77 as a transcriptional regulator of glycolysis in skeletal muscle. More recently, we showed that Nur77 expression also controls myofiber size in mice. It was unknown, however, whether Nur77’s regulation of muscle size begins during developmental myogenesis or only in adulthood. To determine the importance of Nur77 throughout muscle growth, we examined myofiber size at E18.5, 3 weeks postnatal age, and in young adult mice. Using the global Nur77-/- mice, we showed that Nur77 deficiency reduced myofiber size as early as E18.5. The reduction in myofiber size became more pronounced by 3 weeks of age. We observed comparable reduction in myofiber size in young myofiber-specific Nur77-knockout mice. These findings suggest that Nur77’s effect on muscle growth is intrinsic to its expression in differentiating myofibers, and not dependent on its expression in myogenic stem cells. To determine the importance of Nur77 expression in muscle accretion in mature mice, we generated an inducible-, muscle-specific, Nur77-deficient mouse model. We demonstrated that tamoxifen-induced deletion of Nur77 in 3-month-old mice reduced myofiber size. This change was accompanied by increased activity of Smad2 and FoxO3, two negative regulators of muscle mass. The role of Nur77 in muscle growth was further elaborated in the cardiotoxin-induced muscle regeneration model. Compared to wildtype mice, regenerated myofibers were smaller in Nur77-/- mice. However, when normalized to saline-injected muscle, the recovery of sarcoplasmic area was comparable between Nur77-/- and wildtype mice. These findings suggest that Nur77 deficiency compromises myofiber growth, but not the regenerative capacity of myogenic progenitor cells. Collectively, the findings presented here demonstrate Nur77 as an important regulator of muscle growth both during prenatal and postnatal myogenesis.
Muscle wasting is a prevalent problem in disuse, diabetes, cancer cachexia, glucocorticoid excess, HIV, and aging. Skeletal muscle is the dominant site of insulin- and exercise-stimulated glucose disposal and a major target of insulin-sensitizing anti-diabetic medications. Reduced muscle mass impairs ambulatory function, stability, and systemic glucose metabolism. Optimizing muscle mass therefore has the potential to improve glycemic control, prevent disability, and improve quality of life. Uncovering regulatory pathways that control physiological muscle growth provides the basis for understanding and potentially reversing the pathological mechanisms of muscle wasting.
We previously showed that Nur77 expression in skeletal muscle is a determinant of muscle mass in mice. The time course of this regulation remained unknown, however. Here we showed that the reduction in myofiber size was evident in Nur77-deficient mice size as early as E18.5, but became more pronounced by 3 weeks of age, highlighting the importance of Nur77 expression in both fetal and postnatal muscle growth. We further demonstrated in a novel, inducible model of Nur77 deficiency, that loss of Nur77 during adulthood is sufficient to compromise myofiber size, supporting our hypothesis that Nur77 mediates myofiber growth during physiological muscle accretion in adulthood. Muscle mass in the imKO mice was unaffected, however, in contrast to the ~ 10% decrease in muscle mass we observed in the mKO and global knockout mice . We speculate that this difference underscores the importance of muscle Nur77 expression during muscle development, which is unperturbed in the imKO mouse. We also showed in the cardiotoxin-induced muscle regeneration model, that Nur77 expression is not required for myogenic differentiation, but is important in the growth of the regenerated myofibers. Finally, we demonstrated here that the effect of Nur77 on muscle growth is intrinsic to its expression in differentiated muscles, and not from its action in the myogenic stem cell compartment.