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

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 1

Intermittent once-weekly prednisone regimen rejuvenates mitochondrial and mass properties of aging muscle.

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Intermittent once-weekly prednisone regimen rejuvenates mitochondrial an...
(A) Treatment improved strength and treadmill performance in background-matched male mice at young adult (4 mo) and older adult (24 mo) ages, improving the parameters of the treated aged mice to levels comparable to those of the control (veh, vehicle) young adult mice at the endpoint. (B) Treatment rescued specific force in older mice to levels seen in control young mice, while increasing resistance to repetitive tetanus fatigue to a comparable extent at both ages. max, maximum. (C and D) Treatment improved mitochondrial abundance (mtDNA/nDNA, MitoTracker) and decreased superoxide levels (MitoSOX) in aged muscle compared with young control-like levels. Analogous trends were observed with mitochondrial respiration levels and NMR-quantitated levels of ATP and phosphocreatine in quadriceps muscles. AA, antimycin A; FC, fold change; rot, rotenone. (E–G) In treated older mice, total lean mass increased to young control-like levels. This correlated with rescue of muscle weight/body weight ratios in older mice in locomotory (gastrocnemius, quadriceps, triceps) and respiratory (diaphragm) muscles. Tibialis anterior muscle analyses showed coupling of myofiber CSA trends with the changes in muscle mass. n = 4–8/group. Histograms and curves report the mean ± SEM; pre- and post-treatment plots report each subject trend; violin plots indicate the mean and the 25th–75th percentiles. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001; (start-end) pre-/post-paired 3-way ANOVA with Šidák’s test (endpoint) (A and E); 2-way ANOVA with Šidák’s test (B–D, F, and G).