Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance

Wattez, Jean-Sebastien; Eury, Elodie; Hazen, Bethany C.; Wade, Alexa K.; Chau, Sarah; Ou, Shuching; Russell, Aaron P.; Cho, Yoshitake; Kralli, Anastasia

doi:10.1016/j.molmet.2023.101670

Cited by 13 publications

(13 citation statements)

References 53 publications

(86 reference statements)

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“…Increasing SDH/CII flux may be a compensatory mechanism in response to OVX as loss of estrogen has been shown to decrease CI respiration in skeletal muscle 50 . However, this finding contradicts other studies which demonstrate reduced SDH following ovariectomy or ERR KO [51][52][53] . Most likely, our conflicting data is related to either the protocol employed to prevent estrogens' effect on skeletal muscle (i.e., reduced estrogen levels versus KO of the receptor) or the length of time between OVX and testing as estrogen levels can fluctuate due to extragonadal aromatisation of estrogen 49 .…”

Section: Discussioncontrasting

confidence: 96%

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Timpani,

Debrincat,

Kourakis

et al. 2024

Preprint

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Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.

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Section: Discussioncontrasting

confidence: 96%

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Timpani,

Debrincat,

Kourakis

et al. 2024

Preprint

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“…However, activation of NF-κB signaling via the alternative, or non-canonical, pathway has also been demonstrated to trigger mitochondrial biogenesis and to improve the metabolic capacity of skeletal muscle [ 63 , 64 ]. In the baseline differential expression pattern from ET individuals, we not only detected activation signatures for commonly approved transcriptional mediators of skeletal muscle endurance phenotype, like PPARG, TP53, and ESRRA [ 13 , 65 , 66 , 67 , 68 ], but also found indications for enhanced NF-κB activity. Although we cannot distinguish whether this reflects canonical or non-canonical signaling, increased expression of the anti-inflammatory enzyme IDO may hint at the latter [ 69 ].…”

Section: Discussionmentioning

confidence: 94%

The Acute, Short-, and Long-Term Effects of Endurance Exercise on Skeletal Muscle Transcriptome Profiles

Beiter,

Zügel,

Hudemann

et al. 2024

IJMS

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A better understanding of the cellular and molecular mechanisms that are involved in skeletal muscle adaptation to exercise is fundamentally important to take full advantage of the enormous benefits that exercise training offers in disease prevention and therapy. The aim of this study was to elucidate the transcriptional signatures that distinguish the endurance-trained and untrained muscles in young adult males (24 ± 3.5 years). We characterized baseline differences as well as acute exercise-induced transcriptome responses in vastus lateralis biopsy specimens of endurance-trained athletes (ET; n = 8; VO2max, 67.2 ± 8.9 mL/min/kg) and sedentary healthy volunteers (SED; n = 8; VO2max, 40.3 ± 7.6 mL/min/kg) using microarray technology. A second cohort of SED volunteers (SED-T; n = 10) followed an 8-week endurance training program to assess expression changes of selected marker genes in the course of skeletal muscle adaptation. We deciphered differential baseline signatures that reflected major differences in the oxidative and metabolic capacity of the endurance-trained and untrained muscles. SED-T individuals in the training group displayed an up-regulation of nodal regulators of oxidative adaptation after 3 weeks of training and a significant shift toward the ET signature after 8 weeks. Transcriptome changes provoked by 1 h of intense cycling exercise only poorly overlapped with the genes that constituted the differential baseline signature of ETs and SEDs. Overall, acute exercise-induced transcriptional responses were connected to pathways of contractile, oxidative, and inflammatory stress and revealed a complex and highly regulated framework of interwoven signaling cascades to cope with exercise-provoked homeostatic challenges. While temporal transcriptional programs that were activated in SEDs and ETs were quite similar, the quantitative divergence in the acute response transcriptomes implicated divergent kinetics of gene induction and repression following an acute bout of exercise. Together, our results provide an extensive examination of the transcriptional framework that underlies skeletal muscle plasticity.

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“…Surprisingly, while ERRα knockout mice display a decrease in muscle mass [ 14 ], specific loss of ERRα has minimal effects on muscle fiber types [ 13 ], likely compensated by other redundant transcription factors, including the ERRγ isoform [ 59 ]. Indeed, combined loss of ERRα and ERRγ leads to more pronounced adverse effects on muscle functions [ 24 , 25 ]. By contrast, ERRα phospho-mutation at birth activates genetic programs characteristic of oxidative slow-twitch muscle fibers, highlighting ERRα 3SA mice as a valuable model to unmask undiscovered ERRα functions.…”

Section: Discussionmentioning

confidence: 99%

“…ERRα expression has been reported to be transcriptionally induced by exercise in skeletal muscle of both mice and humans [ [21] , [22] , [23] ]. ERRα-null mice display exercise intolerance, an effect found exacerbated by the combined loss-of-function of ERRα and ERRγ in muscle [ 14 , 24 , 25 ]. ERRα targets are also downregulated in muscles of patients with metabolic abnormalities [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

Xia,

Scholtes,

Dufour

et al. 2023

Molecular Metabolism

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Loss of skeletal muscle estrogen-related receptors leads to severe exercise intolerance

Cited by 13 publications

References 53 publications

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice

The Acute, Short-, and Long-Term Effects of Endurance Exercise on Skeletal Muscle Transcriptome Profiles

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

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