The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via<i>Igf1</i>expression in male mice

Abstract Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via extra-myofiber cells or tissues. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with apoptosis and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1, which can increase skeletal muscle mass in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.Significance statement Androgens are essential not only for the development of male sexual characteristics but also for a range of physiological functions, including the regulation of skeletal muscle growth and function. Understanding the functionality of the androgen receptor (AR) is essential for comprehending the mechanisms through which androgens exert their effects on skeletal muscles, as these effects are mediated through AR binding. Our study demonstrates that AR is expressed in mesenchymal progenitors, which play a vital role in muscle homeostasis, and regulates the expression of insulin-like growth factor 1 (Igf1)—a key player in skeletal muscle growth—to control muscle mass. Combining androgens and IGF1 treatments may offer potential therapeutic approaches for addressing muscle atrophy conditions such as sarcopenia..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 22. Apr. Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:	Sakai, Hiroshi [VerfasserIn] Uno, Hideaki [VerfasserIn] Yamakawa, Harumi [VerfasserIn] Tanaka, Kaori [VerfasserIn] Ikedo, Aoi [VerfasserIn] Uezumi, Akiyoshi [VerfasserIn] Ohkawa, Yasuyuki [VerfasserIn] Imai, Yuuki [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2023.11.21.568190

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PPN (Katalog-ID):	XBI041629450