Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model
Ashok D. Prabakaran, … , Brian N. Finck, Mattia Quattrocelli
Ashok D. Prabakaran, … , Brian N. Finck, Mattia Quattrocelli
Published May 3, 2024
Citation Information: J Clin Invest. 2024;134(11):e177427. https://doi.org/10.1172/JCI177427.
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Research Article Aging Muscle biology Article has an altmetric score of 18

Intermittent glucocorticoid treatment improves muscle metabolism via the PGC1α/Lipin1 axis in an aging-related sarcopenia model

Abstract

Sarcopenia burdens the older population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are lacking. The glucocorticoid prednisone remodels muscle metabolism on the basis of frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone administration rescued muscle quality in aged 24-month-old mice to a level comparable to that seen in young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing peroxisome proliferator–activated receptor γ coactivator 1 α (PGC1α) and its cofactor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed myocyte-specific Lipin1 as a nonredundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes for the coordinated rescue of energy and mass in sarcopenia.

Authors

Ashok D. Prabakaran, Kevin McFarland, Karen Miz, Hima Bindu Durumutla, Kevin Piczer, Fadoua El Abdellaoui Soussi, Hannah Latimer, Cole Werbrich, Hyun-Jy Chung, N. Scott Blair, Douglas P. Millay, Andrew J. Morris, Brendan Prideaux, Brian N. Finck, Mattia Quattrocelli

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Figure 2

Epigenetic and transcriptional profiling reveals a treatment-induced muscle GR cistrome that is maintained through aging.

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Epigenetic and transcriptional profiling reveals a treatment-induced mus...
(A and B) Motif analysis and robust promoter peaks in the canonical target Fkbp5 confirm GR ChIP-Seq data sets. (C–E) Treatment increased GR peak numbers and genome-wide, GRE-bound GR signal to comparable extents in both young and older age groups in both males and females. In all experimental groups, treatment increased the GR signal in promoters and 5′-UTR regions. norm, normalized. (F) PCA analysis of RNA-Seq data sets showed age- and treatment-related trends across sexes. (G and H) GO analysis revealed enrichment for muscle metabolic factors, particularly Ppargc1a (encoding PGC1α) and Lpin1 (encoding the PGC1α cofactor Lipin1). veh, vehicle; pred, prednisone. (I) Expression of both isoforms 1 and 4 of Ppargc1a was rescued to young-like levels in treated older muscle, correlating with increased GR binding on canonical and alternative start sites (arrows). TPM, transcripts per million. n = 3/group. Histograms report the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001; 2-way ANOVA with Šidák’s test.