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Myogenin regulates exercise capacity and skeletal muscle metabolism in the adult mouse.

Flynn JM, Meadows E, Fiorotto M, Klein WH - PLoS ONE (2010)

Bottom Line: The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear.This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise.The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear. We sought to determine myogenin's function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we performed indirect calorimetry, monitored blood glucose and lactate levels, and performed histochemical analyses on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle.

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Blood metabolite values in wild-type and Myog-deleted mice after high-intensity exercise.(A) Blood lactate levels. Prior to exercise, Myog-deleted mice exhibited normal levels of blood lactate (Myog-deleted, 3.1 mM; wild-type, 3.2 mM). Exhausted wild-type mice exhibited elevated blood lactate levels (8.6 mM), 2.7-fold higher than pre-exercise levels. At wild-type exhaustion, Myog-deleted mice had blood lactate levels similar to pre-exercise levels. Exhausted Myog-deleted mice exhibited a 4.1-fold increase in blood lactate relative to pre-exercise levels and 1.5-fold higher than exhausted wild-type mice (12.9 mM) (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation (P<0.05). (B) Blood glucose values. Prior to exercise, Myog-deleted mice had normal blood glucose levels compared with wild-type control mice (52 mg/dL). When wild-type mice reached exhaustion, their blood glucose levels were similar to their pre-exercise values (162 mg/dL). At exhaustion, Myog-deleted mice had a 33% reduction in blood glucose relative to levels in wild-type mice at exhaustion (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation. *P<0.05.
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pone-0013535-g003: Blood metabolite values in wild-type and Myog-deleted mice after high-intensity exercise.(A) Blood lactate levels. Prior to exercise, Myog-deleted mice exhibited normal levels of blood lactate (Myog-deleted, 3.1 mM; wild-type, 3.2 mM). Exhausted wild-type mice exhibited elevated blood lactate levels (8.6 mM), 2.7-fold higher than pre-exercise levels. At wild-type exhaustion, Myog-deleted mice had blood lactate levels similar to pre-exercise levels. Exhausted Myog-deleted mice exhibited a 4.1-fold increase in blood lactate relative to pre-exercise levels and 1.5-fold higher than exhausted wild-type mice (12.9 mM) (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation (P<0.05). (B) Blood glucose values. Prior to exercise, Myog-deleted mice had normal blood glucose levels compared with wild-type control mice (52 mg/dL). When wild-type mice reached exhaustion, their blood glucose levels were similar to their pre-exercise values (162 mg/dL). At exhaustion, Myog-deleted mice had a 33% reduction in blood glucose relative to levels in wild-type mice at exhaustion (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation. *P<0.05.

Mentions: Another group of mice was subjected to high-intensity running. When wild-type mice reached exhaustion, their blood lactate levels were elevated 2.7 fold compared with the basal levels of pre-exercised mice whereas after the same amount of exercise, blood lactate levels in the Myog-deleted mice were not different from baseline (Fig. 3A). However, when Myog-deleted mice were run to exhaustion, there blood lactate was elevated 4 fold (Fig. 3A). These highly elevated blood lactate levels were a strong indication of enhanced glycolysis and lactate production in the skeletal muscles of Myog-deleted mice that had been run to exhaustion. Furthermore, at exhaustion Myog-deleted mice had reduced blood glucose levels compared to the wild-type mice (Fig. 3B). Reduced blood glucose was another strong indicator that metabolism processes were enhanced during high-intensity exercise in Myog-deleted mice.


Myogenin regulates exercise capacity and skeletal muscle metabolism in the adult mouse.

Flynn JM, Meadows E, Fiorotto M, Klein WH - PLoS ONE (2010)

Blood metabolite values in wild-type and Myog-deleted mice after high-intensity exercise.(A) Blood lactate levels. Prior to exercise, Myog-deleted mice exhibited normal levels of blood lactate (Myog-deleted, 3.1 mM; wild-type, 3.2 mM). Exhausted wild-type mice exhibited elevated blood lactate levels (8.6 mM), 2.7-fold higher than pre-exercise levels. At wild-type exhaustion, Myog-deleted mice had blood lactate levels similar to pre-exercise levels. Exhausted Myog-deleted mice exhibited a 4.1-fold increase in blood lactate relative to pre-exercise levels and 1.5-fold higher than exhausted wild-type mice (12.9 mM) (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation (P<0.05). (B) Blood glucose values. Prior to exercise, Myog-deleted mice had normal blood glucose levels compared with wild-type control mice (52 mg/dL). When wild-type mice reached exhaustion, their blood glucose levels were similar to their pre-exercise values (162 mg/dL). At exhaustion, Myog-deleted mice had a 33% reduction in blood glucose relative to levels in wild-type mice at exhaustion (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation. *P<0.05.
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pone-0013535-g003: Blood metabolite values in wild-type and Myog-deleted mice after high-intensity exercise.(A) Blood lactate levels. Prior to exercise, Myog-deleted mice exhibited normal levels of blood lactate (Myog-deleted, 3.1 mM; wild-type, 3.2 mM). Exhausted wild-type mice exhibited elevated blood lactate levels (8.6 mM), 2.7-fold higher than pre-exercise levels. At wild-type exhaustion, Myog-deleted mice had blood lactate levels similar to pre-exercise levels. Exhausted Myog-deleted mice exhibited a 4.1-fold increase in blood lactate relative to pre-exercise levels and 1.5-fold higher than exhausted wild-type mice (12.9 mM) (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation (P<0.05). (B) Blood glucose values. Prior to exercise, Myog-deleted mice had normal blood glucose levels compared with wild-type control mice (52 mg/dL). When wild-type mice reached exhaustion, their blood glucose levels were similar to their pre-exercise values (162 mg/dL). At exhaustion, Myog-deleted mice had a 33% reduction in blood glucose relative to levels in wild-type mice at exhaustion (Myog-deleted, n = 6; wild-type, n = 6). Blue bars indicate wild-type control values; red bars indicate Myog-deleted values. Error bars represent one standard deviation. *P<0.05.
Mentions: Another group of mice was subjected to high-intensity running. When wild-type mice reached exhaustion, their blood lactate levels were elevated 2.7 fold compared with the basal levels of pre-exercised mice whereas after the same amount of exercise, blood lactate levels in the Myog-deleted mice were not different from baseline (Fig. 3A). However, when Myog-deleted mice were run to exhaustion, there blood lactate was elevated 4 fold (Fig. 3A). These highly elevated blood lactate levels were a strong indication of enhanced glycolysis and lactate production in the skeletal muscles of Myog-deleted mice that had been run to exhaustion. Furthermore, at exhaustion Myog-deleted mice had reduced blood glucose levels compared to the wild-type mice (Fig. 3B). Reduced blood glucose was another strong indicator that metabolism processes were enhanced during high-intensity exercise in Myog-deleted mice.

Bottom Line: The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear.This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise.The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Although skeletal muscle metabolism is a well-studied physiological process, little is known about how it is regulated at the transcriptional level. The myogenic transcription factor myogenin is required for skeletal muscle development during embryonic and fetal life, but myogenin's role in adult skeletal muscle is unclear. We sought to determine myogenin's function in adult muscle metabolism. A Myog conditional allele and Cre-ER transgene were used to delete Myog in adult mice. Mice were analyzed for exercise capacity by involuntary treadmill running. To assess oxidative and glycolytic metabolism, we performed indirect calorimetry, monitored blood glucose and lactate levels, and performed histochemical analyses on muscle fibers. Surprisingly, we found that Myog-deleted mice performed significantly better than controls in high- and low-intensity treadmill running. This enhanced exercise capacity was due to more efficient oxidative metabolism during low- and high-intensity exercise and more efficient glycolytic metabolism during high-intensity exercise. Furthermore, Myog-deleted mice had an enhanced response to long-term voluntary exercise training on running wheels. We identified several candidate genes whose expression was altered in exercise-stressed muscle of mice lacking myogenin. The results suggest that myogenin plays a critical role as a high-level transcriptional regulator to control the energy balance between aerobic and anaerobic metabolism in adult skeletal muscle.

Show MeSH
Related in: MedlinePlus