Available online 3 September 2023, 101101

Author links open overlay panel, Abstract

Androgens’ pleiotropic actions in promoting sex differences present not only a challenge to providing a comprehensive account of their function, but also an opportunity to gain insights by comparing androgenic actions across organ systems. Although often overlooked by neuroscientists, skeletal muscle is another androgen-responsive organ system which shares with the nervous system properties of electrochemical excitability, behavioral relevance, and remarkable capacity for adaptive plasticity. Here we review androgenic regulation of mitogenic plasticity in skeletal muscle with the goal of identifying areas of interest to those researching androgenic mechanisms mediating sexual differentiation of neurogenesis. We use an organizational-activational framework to relate broad areas of similarity and difference between androgen effects on mitogenesis in muscle and brain throughout the lifespan, from early organogenesis, through pubertal organization, adult activation, and aging. The focus of the review is androgenic regulation of muscle-specific stem cells (satellite cells), which share with neural stem cells essential functions in development, plasticity, and repair, albeit with distinct, muscle-specific features. Also considered are areas of paracrine and endocrine interaction between androgen action on muscle and nervous system, including mediation of neural plasticity of innervating and distal neural populations by muscle-produced trophic factors.

Section snippetsWhy should neuroendocrinologists studying neurogenesis care about skeletal muscle?

There is an unfortunate lack of discourse between those studying the nervous system and those studying muscle. Despite their superficial dissimilarity, these organ systems not only share important features, but also interact directly and indirectly. Both use electrophysiological mechanisms to respond quickly to perturbation (ie., are excitable), and to adaptably change their functional properties with experience, and this plasticity is accomplished in part through mitogenic processes. Both

Androgens and myogenic stem cells throughout the lifespan

Gonadal testosterone mediates many sexually differentiated outcomes in both brain and muscle. Testosterone may have androgenic and/or estrogenic effects in brain and muscle, although in contrast to brain, androgenic effects of gonadal testosterone are believed to predominate in muscle. Consequently, much of the focus of research and intervention has been on androgenic mechanisms. Nonetheless, estrogenic effects on muscle have been described (Unger et al., 2023, Nowacek and Sengelaub, 2006 Aug),

Expression of myogenic regulatory factors

Muscle development and plasticity is largely determined by myogenic regulatory factors including Paired box protein 3 (PAX3) and Paired box protein 7 (PAX7), Myoblast determination protein 1 (MyoD), Myogenic Factor 5 (Myf5), MRF4, and myogenin (Bentzinger et al., 2012), all of which play complex roles which vary by developmental stage (Figure 1). Skeletal muscle formation in embryonic myogenesis consists of PAX3/7+ somite-derived muscle progenitor cells (MPCs) differentiating into SCs, and MPCs

Conclusions and areas for future investigation

In conclusion, we have reviewed evidence that mitogenesis in muscle and brain shares common mechanisms and both have critical roles in development, plasticity and repair. We have also reviewed evidence that androgens regulate this mitogenesis in muscle to organize and activate sex differences in neuromuscular systems. We have endeavored to identify points of intersection between the siloed fields of myogenesis and neurogenesis which offer opportunities for cross-pollination. These areas of

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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