Joe G. Rizk

Glucocorticoids (GCs) exert profound effects on skeletal muscle, but the contribution of satellite cell (SatC) glucocorticoid receptor (GR) signaling to muscle regeneration remains poorly understood. Here, we investigated the role of GR in SatC homeostasis and assessed whether SatC GR mediates the effects of therapeutic GCs on muscle repair. Conditional deletion of GR in SatC reduced the number of PAX7-positive cells during regeneration in young mice, but did not substantially impair muscle repair in either young or aged animals. Transcriptomic and chromatin profiling revealed that GR occupies genes involved in stem cell fate and developmental signaling, with extensive GR binding already established in quiescent SatC. GR-deficient quiescent SatC showed reduced expression of Yap1 , Runx1 and Foxo1 , together with increased Myog expression. Similarly, GR silencing in human myoblasts induced early myogenic differentiation markers without affecting proliferation, supporting a conserved role for GR in restraining myogenic commitment. We next examined the effects of two therapeutic GCs on muscle regeneration. Chronic prednisone treatment altered the transcriptional landscape of regenerating muscle in an age-dependent manner, without substantially affecting histological repair. In contrast, dexamethasone administration during the early inflammatory phase delayed regeneration, with persistent necrosis and increased collagen deposition. These effects were comparable in control and SatC-specific GR-deficient mice, indicating that they do not require GR in SatC. Together, these findings identify GR as a regulator of the quiescent, undifferentiated state of SatC, while showing that the effects of therapeutic GCs on muscle repair are largely independent of SatC GR. They further highlight the importance of treatment regimen and physiological context in determining the effects of GCs on skeletal muscle regeneration.

Male adipose tissue undergoes profound post-pubertal remodeling characterized by the progressive transition of beige adipocytes toward a white adipocyte phenotype. Although androgen signaling has been implicated in adipose tissue biology, its role in beige adipocyte remodeling and metabolic plasticity remains poorly understood. Here we show that androgen receptor (AR) signaling is dynamically activated in inguinal white adipose tissue during the post-pubertal beige-to-white transition in male mice. Inducible deletion of AR in beige adipocytes impaired this remodeling process, resulting in the persistence of multilocular beige-like adipocytes despite reduced thermogenic competence and marked mitochondrial abnormalities. Transcriptomic and cistromic analyses identified AR as a direct regulator of adipocyte metabolic and differentiation programs, whereas immune-related transcriptional signatures in AR-deficient adipose tissue primarily reflected macrophage infiltration and inflammatory remodeling. Loss of AR promoted mitochondrial dysfunction, mitophagy, and altered glucose handling, while cell-autonomous AR silencing in beige adipocytes recapitulated key defects in mitochondrial organization and adipocyte identity. Longitudinal and metabolic challenge studies further demonstrated that AR signaling is required for age-associated adipose remodeling and adaptive beige adipocyte plasticity during high-fat diet feeding and cold exposure. Together, these findings identify AR as a central regulator of beige adipocyte remodeling, mitochondrial homeostasis, and adaptive metabolic function in male adipose tissue.

Glucocorticoids are key regulators of inflammation and tissue repair, yet their precise role in muscle regeneration remains incompletely understood. Here, we investigate the impact of myeloid‐specific glucocorticoid receptor (GR) invalidation on macrophage dynamics and muscle stem cell function following acute injury. We demonstrate that the loss of GR in myeloid cells leads to increased macrophage accumulation, driven by altered proliferation and recruitment, without affecting fibro‐adipogenic progenitor differentiation or satellite cell proliferation and differentiation under steady‐state conditions. Transcriptomic and cistrome analyses at early regeneration stages reveal that GR directly regulates gene networks involved in cell cycle control in myeloid cells. Importantly, administration of dexamethasone during the pro‐inflammatory phase markedly delays muscle regeneration by impairing monocyte‐to‐macrophage transition and promoting macrophage proliferation in a myeloid‐GR‐dependent manner, ultimately reducing satellite cell proliferation and myogenesis. In contrast, dexamethasone treatment during the anti‐inflammatory phase exerts limited effects on muscle recovery. Together, our findings uncover a critical temporal role of GR signaling in myeloid cells in coordinating inflammatory resolution and stem cell function during muscle repair, and highlight the complexity of glucocorticoid actions in regenerative contexts.

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multiomic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR in young adult mice disrupts this balance, precipitating premature cell-cycle entry, skewed division modalities, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

Androgen signalling is essential for prostate secretory functions and epithelial cell maintenance, yet how this signal is translated into a transcriptional output remains poorly understood. Androgens functions are primarily mediated by the androgen receptor (AR), which binds hormone response elements similar to those of other steroid receptors, including the glucocorticoid receptor (GR). Here we show that AR and GR are co-expressed in the prostate epithelium, and co-located within nuclear foci. Moreover, GR promotes the formation and dynamics of AR nuclear condensates, and heterodimerizes with AR in a ligand-binding domain-dependent manner. In addition, subtle variations within the hormone response element sequence direct the co-recruitment of AR and GR into activator or repressor complexes to activate or repress gene expression. Finally, prostate-specific deletion of GR in mice disrupts AR nuclear distribution, impairs AR-dependent gene networks involved in epithelial maintenance, and promotes the expression of genes involved in metabolism and cell cycle, resulting in altered tissue homeostasis. Thus, these findings identify GR as an integral component of the AR transcriptional machinery in epithelial cells of the healthy prostate, and reveal how shared cis-regulatory elements are interpreted to generate distinct transcriptional outcomes.

Mécanismes physiopathologiques de la signalisation des androgènes via leur récepteur dans le muscle squelettique chez la souris: Le muscle squelettique est un tissu hautement spécialisé et plastique, dont le maintien fonctionnel et la capacité de régénération reposent sur une régulation hormonale fine. La signalisation androgénique via le récepteur des androgènes (AR) joue un rôle central dans ce processus, surtout ches les mâles. Dans la myofibre mature, AR soutient les fonctions métaboliques en activant la transcription de gènes impliqués dans la glycolyse, l’oxydation mitochondriale et la contraction. La perte d’AR dans les fibres musculaires entraîne une altération du métabolisme glucidique et lipidique, un recours accru à la dégradation des acides aminés, une accumulation d’ammoniaque et une augmentation du stress oxydatif, favorisant un déclin précoce de la fonction musculaire et une susceptibilité accrue au diabète de type 2 chez les mâles. Dans le cas d’une lésion musculaire, AR est également requis dans les cellules satellites pour assurer une régénération efficace et structurée. Son absence induit une reprogrammation transcriptionnelle caractérisée par une perturbation du cytosquelette, un changement de l’identité métabolique des fibres en régénération vers un profil plus oxydatif, et l’émergence de traits caractéristiques du muscle vieillissant. De plus, l’inactivation d’AR dans les cellules satellites perturbe les interactions avec la niche immunitaire et stromale, compromettant l’intégrité du processus régénératif. Ainsi, AR exerce des fonctions complémentaires dans les myofibres et les cellules satellites, contribuant au maintien de l’homéostasie musculaire et à l’orchestration de la réparation tissulaire.

SUMMARY: Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multi-omic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR in young adult mice disrupts this balance, precipitating premature cell-cycle entry, skewed division modalities, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.