Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor beta (PPARb) in skeletal muscle of transgenic mice that overexpressed PPARb. The following abstract from the submitted manuscript describes the major findings of this work. The Nuclear Receptor Transcription Factor PPARbeta/delta Programs Muscle Glucose Metabolism. Zhenji Gan, Eileen Burkart-Hartman, Dong-Ho Han, Brian Finck, Teresa C. Leone, John Holloszy, and Daniel P. Kelly. To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors, PPARalpha (MCK-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase (Ldh)b/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, interacts with the exercise inducible kinase, AMP-activated protein kinase (AMPK), to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A), in a PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARbeta/delta mice had lower circulating levels of lactate compared to non-transgenic controls, while exhibiting supranormal performance on a high intensity exercise regimen. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training. Keywords: muscle, exercise, nuclear receptors, glucose metabolism, gene regulation

Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor beta (PPARb) in skeletal muscle of transgenic mice that overexpressed PPARb. The following abstract from the submitted manuscript describes the major findings of this work. The Nuclear Receptor Transcription Factor PPARbeta/delta Programs Muscle Glucose Metabolism. Zhenji Gan, Eileen Burkart-Hartman, Dong-Ho Han, Brian Finck, Teresa C. Leone, John Holloszy, and Daniel P. Kelly. To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors, PPARalpha (MCK-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase (Ldh)b/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, interacts with the exercise inducible kinase, AMP-activated protein kinase (AMPK), to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A), in a PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARbeta/delta mice had lower circulating levels of lactate compared to non-transgenic controls, while exhibiting supranormal performance on a high intensity exercise regimen. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training. Keywords: muscle, exercise, nuclear receptors, glucose metabolism, gene regulation RNA from two wild-type (non-transgenic (NTG)) and two PPARbeta overexpressing (MCK-PPARb) mice was analyzed. Two replicates of each are provided.

Project description:Background:Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. Methods:We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7CreER/+; ROSA26mTmG/+ mice. SCs were depleted in Pax7CreER/+; ROSA26DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. Results:Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. Conclusion:The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.

Dataset Information

PPARbeta activation induces rapid changes of both AMPK subunit expression and AMPK activation in mouse skeletal muscle.

Publications

PPARbeta activation induces rapid changes of both AMPK subunit expression and AMPK activation in mouse skeletal muscle.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets