Innately expressed estrogen‐related receptors in the skeletal muscle are indispensable for exercise fitness

Sopariwala, Danesh H.; Rios, Andrea S; Pei, Guangsheng; Roy, Anirban; Silva, Meiricris Tomaz da; Nguyen, Hao Thi Thu; Saley, Addison; Drunen, Rachel Van; Kralli, Anastasia; Mahan, Kristin; Zhao, Zhongming; Kumar, Ashok; Narkar, Vihang A.

doi:10.1096/fj.202201518r

Cited by 11 publications

(15 citation statements)

References 63 publications

(153 reference statements)

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“…Exercise trained mice with HLI experienced smaller declines in muscle power output (Figure 3K) and performed ∼45% more total work (Figure 3L) than the control mice with HLI which carried a large effect size (17 2 = 0.16). These findings are consistent with the multitude of positive effectors of exercise training in the skeletal muscle and vasculature (93, 98, 102–108). It should be noted that exercise training and the control group were all from the C57BL6/J genetic strain of mice and thus have a rapid recovery from HLI.…”

Section: Discussionsupporting

confidence: 85%

A 6-minute Limb Function Assessment for Therapeutic Testing in Experimental Peripheral Artery Disease Models

Palzkill,

Tan,

Tice

et al. 2024

Preprint

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Objective: The translation of promising therapies from pre-clinical models of hindlimb ischemia (HLI) to patients with peripheral artery disease (PAD) has been inadequate. While this failure is multifactorial, primary outcome measures in preclinical HLI models and clinical trials involving patients with PAD are not aligned well. For example, laser Doppler perfusion recovery measured under resting conditions is the most used outcome in HLI studies, whereas clinical trials involving patients with PAD primarily assess walking performance. Here, we develop a 6-min limb function test for preclinical models that assesses muscular performance and hemodynamics congruently. Approach and Results: We developed an in situ 6-min limb function test that involves repeated isotonic (shortening) contractions performed against a submaximal load. Continuous measurement of muscle blood flow was performed using laser Doppler flowmetry. Quantification of muscle power, work, and perfusion are obtained across the test. We performed HLI on several mouse strains: C57BL6J, BALBc/J, and MCK-PGC1a (muscle-specific overexpression of PGC1a). Additional experiments were performed using an exercise intervention (voluntary wheel running) following HLI. The 6-min limb function test was successful at detecting differences in limb function of C57BL6/J and BALBc/J mice subjected to HLI with effect sizes superior to laser Doppler. C57BL6/J mice randomized to exercise therapy following HLI had smaller decline in muscle power, greater hyperemia, and performed more work compared to non-exercise controls with HLI. Mice with muscle-specific overexpression of PGC1a had no differences in perfusion recovery in resting conditions, but exhibited greater capillary density, increased muscle mass and absolute force levels, and performed more work across the 6-min limb function test compared to their wildtype littermates. Conclusion: These results demonstrate the efficacy of the 6-min limb function test to detect differences in the response to HLI where traditional perfusion recovery, capillary density, and muscle strength measures were unable to detect therapeutic differences.

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Section: Discussionsupporting

confidence: 85%

A 6-minute Limb Function Assessment for Therapeutic Testing in Experimental Peripheral Artery Disease Models

Palzkill,

Tan,

Tice

et al. 2024

Preprint

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“…Pathways that were significantly SLU-PP-332 upregulated in both muscle types are shown in Figure D,E. Interestingly, these pathways are quite distinct from those identified as downregulated in the skeletal muscle ERRα/γ double KO mice, where oxidative phosphorylation, TCA cycle, and mitochondrial function genes were well represented . However, we previously showed that SLU-PP-332 induced a similar set of energetic genes/pathways in cardiomyocytes as were downregulated in the skeletal muscle double ERRα/γ KO consistent with SLU-PP-332 activation of ERRs.…”

Section: Resultssupporting

confidence: 60%

“…The ERRs play important roles in the regulation of energy metabolism and fuel selection. Loss of ERRα or ERRγ function leads to reduced muscle oxidative function and reduced functional endurance; ,, thus, pharmacological activation of these receptors may lead to beneficial metabolic effects associated with increased skeletal muscle activity for the treatment of metabolic diseases. In this study, we characterize the ability of a pan ERRα/β/γ synthetic agonist with ∼4-fold ERRα selectivity over ERRγ (SLU-PP-332) to function as an exercise mimetic and improve muscle and metabolic function both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity

et al. 2023

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Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo.Here, we report the identification of a synthetic ERR pan agonist, SLU-PP-332, that targets all three ERRs but has the highest potency for ERRα. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an in vivo chemical tool. SLU-PP-332 increases mitochondrial function and cellular respiration in a skeletal muscle cell line. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. We also observed that SLU-PP-332 induced an ERRα-specific acute aerobic exercise genetic program, and the ERRα activation was critical for enhancing exercise endurance in mice. These data indicate the feasibility of targeting ERRα for the development of compounds that act as exercise mimetics that may be effective in the treatment of numerous metabolic disorders and to improve muscle function in the aging.

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“…59 Subcluster 5 was also found to be enriched with ESRRG expression (Figure S4C and S4D), which has been shown to enhance ischemic angiogenesis and oxidative function of muscle in murine PAD models. 60,61 Coincidentally, PAD type II myonuclei also displayed substantial upregulation of PFKFB3 (Figure S4D), a known stimulator of glycolysis which is also linked to ischemic myopathy. 62 Unsupervised clustering of 5494 hybrid I-II myonuclei generated seven distinct populations (Figure S6A).…”

Section: Patients With Pad Display Unique Myonuclei Populations and T...mentioning

confidence: 95%

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Pass,

Palzkill,

Tan

et al. 2023

Circulation Research

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Background: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. Methods: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas. Results: Single-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. Conclusions: This reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

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Innately expressed estrogen‐related receptors in the skeletal muscle are indispensable for exercise fitness

Cited by 11 publications

References 63 publications

A 6-minute Limb Function Assessment for Therapeutic Testing in Experimental Peripheral Artery Disease Models

A 6-minute Limb Function Assessment for Therapeutic Testing in Experimental Peripheral Artery Disease Models

Synthetic ERRα/β/γ Agonist Induces an ERRα-Dependent Acute Aerobic Exercise Response and Enhances Exercise Capacity

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

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