Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

Quattrocelli, Mattia; Zelikovich, Aaron S.; Jiang, Zhen; Peek, Clara Bien; Demonbreun, Alexis R.; Kuntz, Nancy L.; Barish, Grant D.; Haldar, Saptarsi M.; Bass, Joseph; McNally, Elizabeth M.

doi:10.1172/jci.insight.132402

Cited by 32 publications

(63 citation statements)

References 60 publications

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“…[49][50][51] Additionally, intermittent exposure to GCs is associated with epigenetic programming that enhances nutrient utilization by the co-ordinated action of GR and the transcription factors KLF15 and MEF2C. 52 Intriguingly, similar effects can be observed in other models of neuromuscular diseases, such as the mouse model of spinal muscular atrophy. 53 Thus, the regulatory effects of GRs on KLF15 and muscle gene transcription seem to be context specific.…”

Section: Discussionmentioning

confidence: 93%

Obestatin signalling counteracts glucocorticoid‐induced skeletal muscle atrophy via NEDD4/KLF15 axis

Cid‐Díaz

Leal‐López

Fernández‐Barreiro

et al. 2021

J cachexia sarcopenia muscle

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Background A therapeutic approach for the treatment of glucocorticoid-induced skeletal muscle atrophy should be based on the knowledge of the molecular mechanisms determining the unbalance between anabolic and catabolic processes and how to re-establish this balance. Here, we investigated whether the obestatin/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid-induced muscle atrophy. Methods In this study, we used an in vivo model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin/GPR39 systems. The findings were extended to in vitro effects on human atrophy using human KM155C25 myotubes. Results KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15-triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post-translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin-proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re-establish protein synthesis. Conclusions The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle-related pathologies. These results highlight the potential of the obestatin/GPR39 system to fine-tune the effects of glucocorticoids on skeletal muscle wasting.

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Section: Discussionmentioning

confidence: 93%

Obestatin signalling counteracts glucocorticoid‐induced skeletal muscle atrophy via NEDD4/KLF15 axis

Cid‐Díaz

Leal‐López

Fernández‐Barreiro

et al. 2021

J cachexia sarcopenia muscle

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“…Prednisolone can also improve myofiber maturation in primary myotubes cultured in vitro suggesting that glucocorticoids might also act directly on muscle function (Braun et al, 1989; Sklar and Brown, 1991). In the mdx mouse and in patients, glucocorticoid treatment leads to metabolism reprogramming associated to improved performance of muscles (Quattrocelli et al, 2019). Here we demonstrate that Prednisolone can rescue the branching, fusion and force contraction phenotypes in three different DMD mutant iPSC lines in vitro.…”

Section: Discussionmentioning

confidence: 99%

Prednisolone rescues Duchenne Muscular Dystrophy phenotypes in human pluripotent stem cells-derived skeletal muscle in vitro

Tanoury

Zimmerman

Rao

et al. 2020

Preprint

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Duchenne Muscular Dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced Pluripotent Stem Cells (iPSC) to a late myogenic stage. This allows to recapitulate classical DMD phenotypes (mislocalization of proteins of the Dystrophin-glycoprotein associated complex (DGC), increased fusion, myofiber branching, force contraction defects and calcium hyperactivation) in isogenic DMD-mutant iPSC lines in vitro. Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are due to anti-inflammatory properties. Our work introduces a new human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches.

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“…Recently, we reported data from a retrospective cross-sectional study ( N = 24) comparing daily versus weekend steroid use over five years in groups with comparable body mass indices. Despite similar cumulative doses, DMD patients in the weekend steroid cohort showed lower levels of glycemia, insulinemia, and fat mass and higher lean mass than patients in the daily group [ 131 ]. Additionally, morning cortisol levels were higher in the weekend cohort than in the daily cohort, consistent with the concept of lower suppression of the hypothalamic-pituitary-adrenal axis with intermittent dosing [ 131 ].…”

Section: Glucocorticoids In Dystrophic Musclementioning

confidence: 99%

“…Despite similar cumulative doses, DMD patients in the weekend steroid cohort showed lower levels of glycemia, insulinemia, and fat mass and higher lean mass than patients in the daily group [ 131 ]. Additionally, morning cortisol levels were higher in the weekend cohort than in the daily cohort, consistent with the concept of lower suppression of the hypothalamic-pituitary-adrenal axis with intermittent dosing [ 131 ]. Thus, intermittent steroid dosing appears to mediate steroid benefit with a lower side effect profile, even in the chronic setting.…”

Section: Glucocorticoids In Dystrophic Musclementioning

confidence: 99%

“…Retrospective studies of steroid use in DMD found significant benefits to onset of cardiomyopathy and systolic function decline [ 140, 141 ]. In the study comparing weekend to daily glucocorticoid regimens, no differences were found between treatments on electrocardiography parameters, myocardial thickness or fractional shortening [ 131 ], suggesting intermittent dosing might match daily dosing for cardiac benefits. No data are yet available for vamorolone trials in DMD boys, although heart rate has been included as secondary outcome measure in the ongoing trial (NCT03439670).…”

Section: Glucocorticoids In Dystrophic Musclementioning

confidence: 99%

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Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy

Quattrocelli

Zelikovich

Salamone

et al. 2021

JND

Self Cite

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Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences ranging from adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.

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Pulsed glucocorticoids enhance dystrophic muscle performance through epigenetic-metabolic reprogramming

Cited by 32 publications

References 60 publications

Obestatin signalling counteracts glucocorticoid‐induced skeletal muscle atrophy via NEDD4/KLF15 axis

Obestatin signalling counteracts glucocorticoid‐induced skeletal muscle atrophy via NEDD4/KLF15 axis

Prednisolone rescues Duchenne Muscular Dystrophy phenotypes in human pluripotent stem cells-derived skeletal muscle in vitro

Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy

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