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Adult and Embryonic Skeletal Muscle Microexplant Culture and Isolation of Skeletal Muscle Stem Cells
Published on: September 21, 2010
Nur77 deletion impairs muscle growth during developmental myogenesis and muscle regeneration in mice
Omar Cortez-Toledo1, Caitlin Schnair1, Peer Sangngern1
1The Center for Endocrinology, Diabetes, and Metabolism, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, United States of America.
Abstract:
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.
Insights
Nur77 is crucial for muscle growth from prenatal development through adulthood. Its absence reduces myofiber size, impacting muscle accretion but not regeneration capacity in mice.
Area of Science:
- Muscle biology
- Developmental biology
- Molecular genetics
Background:
- Muscle atrophy is common in aging and illness, necessitating new therapeutic targets.
- Nur77 (nuclear receptor subfamily 7 group C member 1) is a transcriptional regulator involved in skeletal muscle glycolysis and myofiber size.
- The role of Nur77 in muscle development and growth throughout different life stages remained unclear.
Purpose of the Study:
- To investigate the role of Nur77 in muscle growth during prenatal and postnatal development.
- To determine if Nur77 deficiency affects myofiber size in adult mice and during muscle regeneration.
- To elucidate the specific cellular origins of Nur77's effect on muscle mass.
Main Methods:
- Analysis of myofiber size in global Nur77 knockout (Nur77-/-) mice at embryonic day 18.5, 3 weeks, and in young adults.
- Generation and analysis of young myofiber-specific Nur77 knockout mice.
- Generation and analysis of an inducible, muscle-specific Nur77-deficient mouse model in adult mice.
- Assessment of muscle regeneration following cardiotoxin-induced injury in Nur77-/- mice.
- Examination of Smad2 and FoxO3 activity in response to Nur77 deletion.
Main Results:
- Nur77 deficiency led to reduced myofiber size starting at embryonic day 18.5, with more pronounced effects by 3 weeks of age.
- Myofiber-specific Nur77 knockout confirmed its intrinsic role in differentiating myofibers, independent of myogenic stem cells.
- Inducible deletion of Nur77 in adult mice decreased myofiber size and increased activity of negative regulators Smad2 and FoxO3.
- Nur77-/- mice showed smaller regenerated myofibers post-injury, but overall recovery of muscle area was comparable to wildtype, indicating intact regenerative capacity.
Conclusions:
- Nur77 is a critical regulator of skeletal muscle growth during both prenatal and postnatal development.
- Nur77's influence on muscle mass is intrinsic to myofibers and affects muscle accretion in mature animals.
- While Nur77 deficiency impairs myofiber growth, it does not compromise the regenerative potential of muscle progenitor cells.
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