Androgen Signaling in Myocytes Contributes to the Maintenance of Muscle Mass and Fiber Type Regulation But Not to Muscle Strength or Fatigue

Abstract

Muscle frailty is considered a major cause of disability in the elderly and chronically ill. However, the exact role of androgen receptor (AR) signaling in muscle remains unclear. Therefore, a postmitotic myocyte-specific AR knockout (mARKO) mouse model was created and investigated together with a mouse model with ubiquitous AR deletion. Muscles from mARKO mice displayed a marked reduction in AR protein (60-88%). Interestingly, body weights and lean body mass were lower in mARKO vs. control mice (-8%). The weight of the highly androgen-sensitive musculus levator ani was significantly reduced (-46%), whereas the weights of other peripheral skeletal muscles were not or only slightly reduced. mARKO mice had lower intra-abdominal fat but did not demonstrate a cortical or trabecular bone phenotype, indicating that selective ablation of the AR in myocytes affected male body composition but not skeletal homeostasis. Furthermore, muscle contractile performance in mARKO mice did not differ from their controls. Myocyte-specific AR ablation resulted in a conversion of fast toward slow fibers, without affecting muscle strength or fatigue. Similar results were obtained in ubiquitous AR deletion, showing lower body weight, whereas some but not all muscle weights were reduced. The percent slow fibers was increased, but no changes in muscle strength or fatigue could be detected. Together, our findings show that myocyte AR signaling contributes to the maintenance of muscle mass and fiber type regulation but not to muscle strength or fatigue. The levator ani weight remains the most sensitive and specific marker of AR-mediated anabolic action on muscle.

NRIP is a novel Z-disc protein to activate calmodulin signaling for skeletal muscle contraction and regeneration

“…However, the resistance of wild-type females to fatigue was greater than wild-type males (Fig. S2C), consistent with previous reports (MacLean et al, 2008;Ophoff et al, 2009); similarly, the resistance of NRIP-knockout females to fatigue was higher than NRIP-knockout males (Fig. S2D).…”

Muscle-specific androgen receptor deletion shows limited actions in myoblasts but not in myofibers in different muscles in vivo

“…Most mARKO models have focused on the LA muscle because it is atypical in its androgen-responsiveness and shows a large reduction in muscle mass, whereas hind-limb muscle mass is normal or near-normal (Ophoff et al 2009b, Chambon et al 2010, Dubois et al 2014. Our mAR ΔZF2 lines also show a similar lack of hind-limb muscle phenotype, despite the fact that global AR ΔZF2 males have a 15-20% decrease in hind-limb muscle mass (MacLean et al 2008b).…”

“…Different studies have suggested that androgens act on satellite cells or myoblasts to increase the number of myonuclei (Mulvaney et al 1988, Joubert et al 1994, Joubert & Tobin 1995 or act on myofibers to increase protein content (Sheffield-Moore et al 1999, Ferrando et al 2002, Chen et al 2008, Ophoff et al 2009b. However, despite the fact that the AR is deleted by ≥93% in hind-limb muscles of both mAR ΔZF2 lines in our study, muscle mass is virtually normal with only relative muscle mass decreased in α-actin mAR ΔZF2 TA and soleus, but all other hind-limb muscles not different to AR lox controls.…”

The biological and clinical advances of androgen receptor function in age-related diseases and cancer [Review]

“…Contractile analyses indicated that fast-twich muscles from male mutants produced less force, whereas their slow-twich muscles had increased fatigue resistance [81]. In the analysis of a myocyte-specific ARKO (M-ARKO) mouse, it was found that myocytic AR transduces androgen-dependent postnatal fiber hypertrophy in perineal but not in limb skeletal muscles [82]. Elevation of slow-twich fibers and reduced fasttwich muscle fibers were also displayed in M-ARKO, suggeating the myocytic AR functions to generate maximum force of fast-and intermediary-twitch leg muscles by controlling myofibrillar organization of androgen-induced hypertrophic myofibers.…”

“…Elevation of slow-twich fibers and reduced fasttwich muscle fibers were also displayed in M-ARKO, suggeating the myocytic AR functions to generate maximum force of fast-and intermediary-twitch leg muscles by controlling myofibrillar organization of androgen-induced hypertrophic myofibers. However, whether muscle strength and fatigue were regulated by AR or not is still controversial [82,83].…”