Fphys 11 621226

MINI REVIEW
published: 15 January 2021

doi: 10.3389/fphys.2020.621226
Links Between Testosterone,

Oestrogen, and the Growth
Hormone/Insulin-Like Growth Factor
Axis and Resistance Exercise Muscle
Adaptations
Nima Gharahdaghi, Bethan E. Phillips, Nathaniel J. Szewczyk, Ken Smith,
Daniel J. Wilkinson* and Philip J. Atherton*
Medical Research Council-Versus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham National Institute for
Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby,
United Kingdom
Maintenance of skeletal muscle mass throughout the life course is key for the regulation of
health, with physical activity a critical component of this, in part, due to its influence upon
key hormones such as testosterone, estrogen, growth hormone (GH), and insulin-like
Edited by: growth factor (IGF). Despite the importance of these hormones for the regulation of
James P. Fisher,
The University of Auckland,
skeletal muscle mass in response to different types of exercise, their interaction with
New Zealand the processes controlling muscle mass remain unclear. This review presents evidence
Reviewed by: on the importance of these hormones in the regulation of skeletal muscle mass and their
Xu Yan, responses, and involvement in muscle adaptation to resistance exercise. Highlighting
Victoria University, Australia
Vladimir Stich, the key role testosterone plays as a primary anabolic hormone in muscle adaptation
Charles University, Czechia following exercise training, through its interaction with anabolic signaling pathways
*Correspondence: and other hormones via the androgen receptor (AR), this review also describes the
Philip J. Atherton
[email protected]
potential importance of fluctuations in other hormones such as GH and IGF-1 in concert
Daniel J. Wilkinson with dietary amino acid availability; and the role of estrogen, under the influence of
[email protected] the menstrual cycle and menopause, being especially important in adaptive exercise
responses in women. Finally, the downstream mechanisms by which these hormones
Specialty section:
This article was submitted to impact regulation of muscle protein turnover (synthesis and breakdown), and thus muscle
Clinical and Translational Physiology, mass are discussed. Advances in our understanding of hormones that impact protein
a section of the journal
Frontiers in Physiology turnover throughout life offers great relevance, not just for athletes, but also for the general
Received: 25 October 2020
and clinical populations alike.
Accepted: 18 December 2020
Keywords: hormone, resistance exercise, muscle growth, protein synthesis, hypertrophy
Published: 15 January 2021
Citation:
Gharahdaghi N, Phillips BE, INTRODUCTION
Szewczyk NJ, Smith K, Wilkinson DJ
and Atherton PJ (2021) Links Between
Skeletal muscle accounts for ∼40–45% of total body mass (Romagnoli et al., 2020). Following a
Testosterone, Oestrogen, and the
Growth Hormone/Insulin-Like Growth
rapid post-natal growth phase, skeletal muscle mass is typically maintained at a steady state in
Factor Axis and Resistance Exercise adulthood through a controlled balance between muscle protein synthesis (MPS) and breakdown
Muscle Adaptations. (MPB)—unless in the presence of physiological (exercise) or pathological (age or disease) stimuli.
Front. Physiol. 11:621226. The mitigation of age and disease-related muscle wasting and dysfunction remains a major research
doi: 10.3389/fphys.2020.621226 effort. Even today after significant efforts to develop pharmaceutical strategies to mitigate muscle
Frontiers in Physiology | www.frontiersin.org 1 January 2021 | Volume 11 | Article 621226

Gharahdaghi et al. Hormones and Exercise Muscle Adaptations
wasting (Sepulveda et al., 2015), contractile activity in the potent hormone due to its receptor binding kinetics (Ly et al.,
form of resistance exercise (RE) remains the most efficacious 2001); however, testosterone has also been shown to regulate
intervention. RE training (RET) leads to muscle hypertrophy a multitude of ergogenic, anabolic, and anti-catabolic functions
through a sustained elevation of MPS (Hooper et al., 2017)— in skeletal muscle, without prior conversion to DHT (Bhasin
responses which are driven by a combination of mechanical et al., 2003). Testosterone also effects the development of bone,
overload, and an associated release of hormones; e.g., androgens connective and neural tissues (Hoffman et al., 2009), leading to
and insulin-like growth factor-1 (IGF-1) (Romagnoli et al., 2020) increased muscle strength, power, endurance, and hypertrophy
and by muscle mechano-sensitive signals. in a dose-dependent manner (Sinha-Hikim et al., 2006; Kraemer
While the fundamental roles of hormones in muscle et al., 2017). The importance of androgens for mediating muscle
development and their decline in aging are well-established, growth are substantiated through numerous lines of evidence,
the impact of physiological fluctuations (e.g., due to circadian including: (1) that exogenous administration, potentiates gains
rhythms or transient increases following bouts of RE) in in muscle strength and muscle mass (Gharahdaghi et al.,
hormones remains unclear (Schroeder et al., 2013). RE 2019); (2) that gonadotropin-releasing hormone analogs, which
induces marked anabolic hormone responses, in particular inhibit endogenous testosterone release, prevent gains in muscle
those involving testosterone, growth hormone (GH) and IGF-1 strength and attenuate gains in muscle mass (Kvorning et al.,
(Spiering et al., 2008). These hormonal elevations in response to 2007); and (3) that AR antagonists, which inhibit endogenous
RE take place in a unique physiological environment, whereby testosterone from binding to the AR, impair radical muscle
acute elevations in circulating blood hormone concentrations, growth during synergist overload (Inoue et al., 1994). Together,
resulting from a combination of either e.g., increased secretion, these findings suggest a significant role for testosterone in
reduced hepatic clearance, reduced plasma volume or reduced regulating adult muscle growth in response to mechanical
degradation rates—interact with receptors on the target tissue loading (i.e., RE).
cell membranes or with nuclear/cytoplasmic receptors located
within the target tissue (e.g., steroid receptors); which, alongside
mechano-signaling, initiates a sequence of molecular events,
Exercise-Induced Testosterone Release,
leading to muscle adaptive responses such as an increase in MPS and Links With Muscle Adaptation by Sex
and/or a decrease in MPB (Kraemer and Ratamess, 2005). Given and Age
the apparent complexity of RE-induced hormonal responses and The relationship between RE and testosterone responses have
their impact on muscle adaptation, we aim to provide an update been extensively reviewed in young men (Ahtiainen et al.,
on advances in this area. 2003, 2005; West et al., 2009; West and Phillips, 2012),
with the majority of studies suggesting that it is the acute
transient elevations in testosterone that likely drive the proposed
TESTOSTERONE hormonal adaptations associated with muscle growth. For
example, immediately following RE, serum testosterone levels
The principal androgen, testosterone, is an anabolic-androgenic peak [∼from 13 (resting levels) to 38 (at ∼30 mins) nmol.L−1 ]
steroid hormone which is synthesized from cholesterol— with a concomitant upregulation of AR mRNA and protein
produced mainly in Leydig cells in men, and the ovary content within the muscle (Willoughby and Taylor, 2004; Hooper
(25%) and adrenalzona fasciculata (25%) in women, via et al., 2017). It seems high intensity RE stimulates basophilic
conversion from progesterone, with the remaining ∼50% being cells of the anterior pituitary to release luteinizing hormone
produced from circulating androstenedione (Burger, 2002). (LH) from gonadotrophs in the anterior pituitary which then
Homeostatic processes maintain systemic testosterone levels acts as the primary regulator of testosterone secretion from the
within the range of 7.7–29.4 nmol.L−1 in healthy young men Leydig cells of the testes (Fry and Kraemer, 1997). High affinity
and 0.1–1.7 nmol.L−1 in healthy menstruating women under binding of LH at the Leydig cells of the testes activates a cyclic
40 y (Handelsman et al., 2018). In contrast, there are no adenosine mono phosphate (cAMP) mechanism, resulting in
differences observed between men and women in relation to increased testosterone synthesis (Dufau and Catt, 1979; Fry and
intramuscular testosterone concentrations and steroidogenic Kraemer, 1997). This activation is dependent on the frequency
enzymes (Vingren et al., 2008). Systemic testosterone is taken and amplitude of LH secretion, with pulses occurring in the
up by the muscle through its binding to membrane-bound human at the rate of ∼8–14 pulses.day−1 in men. Secretion of
or cytoplasmic androgen receptors (AR), in turn stimulating LH is principally regulated by LH releasing hormone (LHRH)
subsequent myocellular signaling (Vingren et al., 2010; Kraemer via portal circulation from the hypothalamus. High affinity
et al., 2020) and altering the expression of thousands of genes, binding of LHRH in the anterior pituitary activates LH secretion
many of which are involved in the regulation of skeletal muscle by a calcium-dependent mechanism, resulting in LH secretion
structure, fiber type (Dubois et al., 2014), intramyocellular (Dufau and Catt, 1979; Fry and Kraemer, 1997). Further, early
metabolism (White et al., 2013), and mRNA transcription increased circulating testosterone levels during RE are also
(MacLean et al., 2008) (Figure 1). Once bound to the AR, LH-independent and it seems they may be directly stimulated
testosterone is irreversibly converted to dihydrotestosterone via increases in lactate levels induced by an increase in the
(DHT) through the enzymatic action of 5-α reductase (Wilborn production of cAMP in testicular tissues (Lin et al., 2001).
et al., 2010). It is generally accepted that DHT is the more However, the mechanisms of lactate action on testosterone

FIGURE 1 | Signaling pathways regulated by testosterone, growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are induced by resistance exercise (RE). RE
has been shown to increase the concentration of these hormones which activate several different signaling pathways in the muscle. These pathways lead to increases
in muscle protein synthesis (MPS) and net protein accretion which result in an increase in muscle mass. SC, satellite cell; AR, androgen receptor; IRS, insulin receptor
substrate; ARE, androgen response element. *Dashed outline represents inhibitory protein cascades.
production by Leydig cells are not clear yet. While the acute responses in young males can be influenced by many factors
response of testosterone returns to baseline rapidly post exercise e.g., timing of sampling etc. Additionally, there is evidence that
and has been shown to not be elevated chronically following RE loads of <70% 1-RM (Tremblay et al., 2004; Yarrow et al.,
repeated bouts of RE (Hooper et al., 2017); the acute upregulation 2007; Fry and Lohnes, 2010; Hough et al., 2011); programs
of AR mRNA and protein content can last up to 1–2 days post incorporating only upper body exercises, even at a relatively
RE (Ratamess et al., 2005), thereby augmenting testosterone high intensity and volume (Migiano et al., 2010); and those with
uptake into the muscle, and potentiating the anabolic effects of the long rest periods between repetitions do not stimulate a
testosterone over longer periods (Murphy and Koehler, 2020; significant post exercise testosterone response (McCaulley et al.,
Tinline-Goodfellow et al., 2020). It therefore may be that the 2009), despite post exercise increases in MPS, anabolic signaling
combined effects of acute testosterone elevation post exercise and associated muscle growth adaptive responses being observed
and sustained AR upregulation in the muscle may represent an (West et al., 2009; West and Phillips, 2012). In an attempt
additional mechanism through which RE might regulate muscle to better understand the discrepancies between testosterone
growth. Notably, while some studies have indicated correlative and muscle adaptive responses, Phillips and colleagues devised
relationships between RE-induced elevations in testosterone and a unique experimental approach, whereby they compared a
muscle strength and hypertrophy (Hansen et al., 2001; Ahtiainen “high” vs. “low” hormone environment (induced by working
et al., 2003, 2005), this remains equivocal (West et al., 2009; distinct muscle bulk) (West et al., 2010). Despite the contrasting
West and Phillips, 2012) perhaps since the magnitude of acute hormonal profiles and significantly different acute testosterone

responses in these environments, muscle mass and strength circulating testosterone in both men and women (Kraemer
gains were comparable, suggesting that the role of testosterone et al., 1998; Hakkinen et al., 2000), with these reductions
(and other hormones) in exercise induced muscle adaptation leading to osteoporosis in both sexes (Mohamad et al., 2016).
is minimal. Conversely, other studies using similar procedures Testosterone is ∼98% bound to serum proteins (sex hormone-
reported that the “high” hormone environment potentiated binding globulin (SHBG) and albumin) and only 1–2% of
muscle strength gains after 9 weeks RET (Hansen et al., 2001) testosterone is unbound or free. Because testosterone is bound
and acute AR content 180 min after RE (Spiering et al., 2009), to SHBG with high affinity, it is not available to most tissues
which was associated with increased MPS, muscle growth and for action. Given the concentration of SHBG increases across
recovery (Sheffield-Moore, 2000). The differences in outcomes the lifespan in men (Liu et al., 2007) and only increase after
between these studies may be driven by the experimental design ∼60 y in women (Maggio et al., 2008), bioavailable testosterone
(different biopsy location; i.e., biceps brachii vs. vastus lateralis (free plus albumin-bound testosterone) concentrations decline
and different testosterone inducing exercise regimes, which even more markedly than total testosterone levels with aging
resulted in different peak testosterone; i.e., 27 (West et al., (Matsumoto, 2002). This reduction can eventually lead to very
2010) vs. 38 nmol.L−1 (Spiering et al., 2009) and also the time low resting concentrations of circulating testosterone particularly
course of muscle sampling (between 3 and 4 h post-RE). These in men, creating the so-called andropause (Vingren et al.,
differences may be important since the duration and magnitude 2010). Intriguingly, this reduction in testosterone tracks with the
of testosterone and AR elevation and AR exposure to testosterone gradual decline in muscle mass observed with age, i.e., ∼1–3%
appear to play a crucial role in skeletal muscle adaptations both decline in circulating testosterone and 1–2% loss of muscle mass
in vitro (Bloomer et al., 2000) and in vivo (Antonio et al., in men (Vingren et al., 2010; Gharahdaghi et al., 2019), perhaps
1999; Ferrando et al., 2002). In turn, as the pituitary-gonadal suggesting declines in endogenous testosterone may be linked to
axis works in a negative feedback loop, increasing AR content loss of muscle mass. Moreover, while RE in older men (> 59
will likely result in enhanced tissue uptake of testosterone, yr old) still elicits an acute elevation in circulating testosterone,
thus lowering circulating testosterone. Reductions in circulating the magnitude of elevation is smaller than that of younger men
testosterone concentrations (due to enhanced cellular uptake) are performing the same RE (Kraemer et al., 1998; Hakkinen et al.,
monitored by the hypothalamus, which releases gonadotropin- 2000), i.e., ∼1 nmol.L−1 in young vs. ∼0.1 nmol.L−1 in older
releasing hormone (GnRH) to stimulate LH secretion, then men (Brook et al., 2016), ostensibly leading to reduced muscle AR
testosterone synthesis/secretion (Kraemer et al., 2006). Herein, it content, MPS and ultimately blunted muscle adaptive responses
is suggested that AR protein content itself may be critical in RE- to chronic RET (Brook et al., 2016; Gharahdaghi et al., 2019).
induced skeletal muscle protein accretion, with AR content, and With provision of exogenous testosterone helping to restore this
not circulating testosterone being more closely associated with blunting somewhat (Gharahdaghi et al., 2019), the influence of
adaptations in muscle mass (Morton et al., 2018) and fiber CSA testosterone on muscle may be small and permissive in the young,
(Mitchell et al., 2013) in young men. but the need for hormonal input for the control of muscle mass
Whilst the majority of investigations into the role of may be more important as we age to overcome age-related deficits
testosterone in muscle adaptive response have been performed in the responsiveness of older muscle to exercise training.
in males (reflecting male biology), the importance of circulating
concentrations of testosterone in adult women should not be
underestimated based on its biological role in the conversion Metabolic and Molecular Effects of
of progesterone to the principal oestrogens—oestradiol and Testosterone in Skeletal Muscle
oestrone (Cui et al., 2013). That being said, the importance of Anabolic effects of AR and testosterone upregulation after
testosterone in women remains unclear since while there is an RE occur through a combination of both genomic i.e.,
indispensable role e.g., on bone health, in older males (Mohamad transcriptional capacity, and non-genomic i.e., translational
et al., 2016), a reduction in testosterone generally does not occur efficiency, pathways (Kraemer et al., 2020). RE and androgens
independently of other hormones (such as the oestrogens) in up-regulate muscle AR content via distinct mechanisms; RE
females (e.g., following the menopause) (Chakravarti et al., 1976). increases AR mRNA transcription via RhoA (a member of
Moreover, females do not have Leydig cells; the cells which are the Rho family of small GTPases which is involved in muscle
likely the source of the acute RE-induced increase in testosterone transcription factor) and serum response factor (MADS-box
in men (Kvorning et al., 2007). That said, increases in testosterone transcription factor which is essential for muscle-specific gene
in females have been reported in response to RE in some (Nindl expression) signaling (Lee et al., 2003); in contrast, testosterone
et al., 2001; Copeland et al., 2002), but not all (Marx et al., increases muscle AR via enhanced AR mRNA association with
2001; Linnamo et al., 2005) studies, albeit with claims of no, polyribosomes, increasing AR mRNA translation (Mora and
or limited, effects of acute testosterone elevations in relation to Mahesh, 1999) and doubling AR half-life from ∼3.1 to 6.6 h
muscle growth in women (Kraemer et al., 2017). Therefore, the (Syms et al., 1985). Due to these contrasting mechanisms
links between the testosterone response and exercise adaptation of action, a combination of RE and RE-induced testosterone
in women remain contentious and require further investigation. secretion will likely potentiate post exercise AR responses for
Finally, it is important when overviewing the role of longer, thereby augmenting adaptive muscle growth. Conversely,
testosterone in controlling muscle mass, to consider older impaired testosterone responsiveness to RE in older adults, likely
adults. With aging, there is a linear decline in bioavailable attenuates the AR response, due to lack of testosterone mediated

AR increases, and subsequently, limits muscle mass gains with and Bulun, 2001; Luk et al., 2015); in turn explaining the
RET. When testosterone binds to the AR, the AR transforms, effects of RE-induced testosterone increase on an increase in
dimerizes and translocates to the nucleus, binding to androgen- estrogen levels in women (Luk et al., 2015). The effects of acute
response elements (ARE) therein, as a homodimer. Activation estrogen release may relate to a reduction in exercise-induced
of these AREs stimulates the transcription of protein targets muscle damage and improved recovery (Hansen, 2018), possibly
and other anabolic systems, such as the local production of via its indirect antioxidant properties and stabilization of cell
IGF-1 which is related to muscle protein accretion through membranes (Paroo et al., 2002) and decreased post-exercise
a decrease in IGFBP-4 mRNA concentration coupled with an production of protein chaperones- i.e., heat shock protein (HSP)
increase in IGF-1 mRNA (Bamman et al., 2001; West et al., 72 (Paroo et al., 1999) and HSP70 (Enns and Tiidus, 2010). HSPs
2010) (see IGF-1 section). In addition to these genomic signaling act as an index of cellular damage and activate inflammatory
pathways, testosterone is thought to independently activate the cell populations (e.g., neutrophils and macrophages) thereby
Akt/mTOR/S6K1 pathway, which represents an integrated step regulating the extent of inflammatory responses after muscle
in the hypertrophic response (Basualto-Alarcón et al., 2013); and injury (Senf et al., 2013). In addition, estrogen is also known to
also through activation of G protein-linked membrane receptors, activate insulin/IGF-1 (Lee et al., 2004) and PI3K/Akt (Mangan
which result in calcium dependent phosphorylation of ERK1/2 et al., 2014) pathways, potentially enhancing the mechanisms
(a mitogen-activated protein kinases), potentially leading to the regulating MPS (Hansen et al., 2012) and consequently muscle
phosphorylation of transcription factors associated with cellular growth (Smith et al., 2014). The latter is suggested to occur
growth (Kadi, 2008). However, transient activation of ERK1/2 through increased expression of Pax7 and MyoD transcription
induced by testosterone was not found to be directly related factors (Thomas et al., 2010; Sambasivan et al., 2011) which
to the hypertrophic signaling cascade; though activated ERK induce satellite cell expansion, differentiation, and self-renewal
can phosphorylate co-activators of the intracellular receptor at of muscle function and mass (Kitajima and Ono, 2016; Chidi-
the nuclear level (Bratton et al., 2012), through potentiation Ogbolu and Baar, 2019). Given that estrogen stimulates post-
of estrogen receptor activation function 1 (AF-1) by Src/JNK RE myogenesis, decreased estrogen levels in post-menopausal
(serine 118-Independent pathway) which promotes cellular women may be a contributing factor to the development of
growth (Feng et al., 2001; Estrada et al., 2003). In sum, the sarcopenia, diminishing the rate of muscle repair and adaptive
combined effects of RE and RE-induced testosterone release capacity in older women (Thomas et al., 2010). Indeed estrogen
induced upregulation of AR anabolism is driven via genomic and replacement has been shown to attenuate the age-related decline
non-genomic signaling pathways which likely augment protein in muscle mass observed in postmenopausal women (Enns and
turnover in muscle resulting in increases in net protein accretion Tiidus, 2010). However, the proposed effects of estrogen may be
and hypertrophy (Wolfe et al., 2000; Roberts et al., 2018). defined by the stage of the menstrual cycle. For example, low
estrogen in the early follicular stage, may negatively affect RE-
induced increases in estrogen levels (Hansen et al., 2012), while,
METABOLIC AND MOLECULAR EFFECTS in the luteal phase where circulating progesterone is relatively
OF EXERCISE ON OESTROGEN IN high, may also counteract the sensitizing effects of estrogen on
SKELETAL MUSCLE muscle impairing any benefit of acute RE-induced during these
phases (Hansen, 2018). In contrast, RET in the late part of the
Oestrogens are steroid hormones, primarily produced in the follicular phase, when circulating estrogen is enhanced, appears
ovaries from testosterone via an aromatase enzyme, of which to result in increased fiber type II CSA, nuclei to fiber ratio
women have four times the amount compared with men, until and muscle mass, compared to RET during luteal phase (Sung
the menopause (Hansen and Kjaer, 2014). While less studied in et al., 2014; Wikström-Frisén et al., 2017). However, this has
this sphere, endogenous oestrogens seem to have a metabolic not been confirmed (Miller et al., 2006; Sakamaki-Sunaga et al.,
role in regulating skeletal muscle; for instance, being critical 2016) as no differences between follicular phase and luteal phase
for the regrowth of atrophied skeletal muscle (Sitnick et al., RET responses have also been observed, at least with regard to
2006)- an action mediated by the estrogen receptors, located strength gains and hypertrophy; and as such, the role of estrogen
within skeletal muscle tissue that function as transcription in mediating responses to RE, remains unclear. Future trials are
factors (Hansen and Kjaer, 2014). Indeed, as with testosterone needed to clarify the effects of the oestrogens on muscle biology
(and perhaps as a function of its metabolic regulation through under different conditions e.g., phase of menstrual cycle, pre or
testosterone), estrogen is believed to be important in the post-menopause, and the response to nutrition (fasting/feeding)
regulation of both muscle function (Chidi-Ogbolu and Baar, and exercise training (Hansen, 2018).
2019) and hypertrophy in response to exercise—with rapid
changes in systemic concentration occurring immediately post
RE, that are dependent upon RE intensity (Copeland et al., GROWTH HORMONE (GH), EXERCISE,
2002), however, baseline circulating concentrations are unaltered AND EFFECTS ON MUSCLE METABOLISM
following chronic RET for up to 6 months (Gil et al., 2012;
Yoon et al., 2018). It is reported that RE acutely augments Human growth hormone (GH) is secreted from somatotroph
the activity of the aromatase enzyme which results in an cells of the anterior pituitary. It is released in 6–8 bursts.day−1 ,
increase in the biosynthesis of estrogen from androgens (Nelson with negligible secretion outside of these bursts, and is under the

control of the hypothalamic hormones: GH-releasing hormone and long term muscle and fiber type I and II hypertrophy (McCall
(GHRH), which promotes secretion, and somatostatin which et al., 1999). GH per se has also been associated with whole body
inhibits release of GH (Giustina et al., 2008). Following protein synthesis (e.g., reflecting in part, connective tissues); but
GH release, which induces the hepatic generation of IGF-1, directly, may not augment MPS (Doessing et al., 2010; West et al.,
circulating levels of IGF-1 and GH, feedback to the hypothalamus 2010). Conversely, acute GH infusion studies (eliciting a similar
to inhibit further GH secretion (Daughaday, 2000). RE is the to post RE increase in GH levels) have shown this hormone may
most potent physiological stimulus for GH release in both have a role in stimulating MPS (Fryburg et al., 1991; Fryburg and
men (Nicholls and Holt, 2016; Fink et al., 2017) and women Barrett, 1993) while associated increases in insulin inhibit MPB
(Hymer et al., 2001), but little is known about how RE alters (Fryburg et al., 1992). Thus, while GH is a positive regulator
somatotroph content and function. GH begins to rise 10–20 min of extracellular matrix (ECM) synthesis (Kragstrup et al., 2011)
after commencing RE and peaks at the end of the RE (Gibney which is important in morphogenesis (Rozario and DeSimone,
et al., 2007; Fink et al., 2018a), returning to baseline values 2010), there is still debate surrounding its role in the regulation
around 60 min post RE (Häkkinen and Pakarinen, 1995; Fink of muscle mass in adults; however what may be key is the lack
et al., 2018a). RE increases the amplitude of each GH pulse rather of effect on muscle function regardless of its impact on growth
than the frequency. Accordingly, whole-body RE induces GH pathways and MPS.
increases from basal levels of 5 ug.L−1 (Fink et al., 2018b) to 24 In terms of mechanisms, following release, GH binds to
ug.L−1 (Kraemer et al., 1990) while localized RE of individual its receptor leading to the recruitment and phosphorylation of
muscle groups (biceps and triceps) leads to increases of only half Janus kinase 2 (JAK2) and its most recognized downstream
of this; up to 12 ug.L−1 (Fink et al., 2018a). These increases in target, signal transducer and activator of transcription 5 (STAT5)
post RE GH levels are blunted in older adults, and a progressive (Jørgensen et al., 2006). In addition, GH stimulates the IRS1/Akt
decline in GH secretion and clearance is observed after the age of (Costoya et al., 1999; Consitt et al., 2017) and mitogen-activated
40 y (Zaccaria et al., 1999). In younger adults, exercise-induced protein kinase (MAPK) pathways which are thought to be
GH release is relatively non-specific occurring in response to both the main pathways contributing to GH/IGF-1-induced muscle
RE and aerobic exercise (e.g., 60% VO2 max) (Godfrey et al., hypertrophy via p42/p44 and p38 pathways (Consitt et al.,
2003). It has also been reported that when lactate is elevated 2017) (Figure 1). The activation of Akt results in skeletal muscle
beyond anaerobic threshold, which is associated with greater growth/maintenance since it controls the phosphorylation of a
demands on anaerobic glycolysis, the hypothalamus is highly number of substrates involved in MPS including mTOR (and its
stimulated (Kraemer et al., 1990, 1993; Hartman et al., 1993). This downstream targets 4E-binding protein 1 (4E-BP1) and p70S6
is further supported during RE protocols of moderate intensity kinase) and glycogen synthase kinase 3β (GSK3β), as well as, the
(10-RM vs. 5-RM) with short rest periods (1 vs. 3 min) between inhibition of protein degradation via the forkhead transcription
sets (Hoffman et al., 2003), which result in higher circulating factor (FOXO) pathway (Consitt et al., 2017). To support these
concentrations of GH in both men and women (Kraemer et al., molecular effects that GH has on muscle mass, GH receptor
1993). The exact mechanism of exercise-induced GH release knock-out results in a decrease in myofiber CSA and muscle
remain ill-defined, however are likely driven via higher intensities mass loss in mice (Sotiropoulos et al., 2006). Nevertheless, as
of RE directly stimulating the anterior pituitary, facilitated via these mice had a reduction in circulating IGF-1 and tissue IGF-
increasing circulating of catecholamines, lactate, nitric oxide and 1 expression; at least in part GH dependent, it is difficult to
changes in acid-base balance (Godfrey et al., 2003). Increases separate the effects of the two hormones (Velloso, 2008) and
in post RE GH levels have also been associated with increased further investigations are needed to clarify the main effects of GH
estrogen levels in women; i.e., area under curve (AUC) of increase on muscle growth in adults, in particular after RE. However, the
in GH after RE was higher in midluteal phase than increases main muscle anabolic effects of GH are believed to be indirect—
in early follicular phases of menstrual cycle (Nakamura et al., via inducing the hepatic generation of IGF-1 triggering the IGF-
2011). It seems there is a close interplay between estrogen levels 1-Akt-mTOR pathway; in turn resulting in MPS augmentation
and GH secretion and prevailing estrogen concentrations may and as a consequence muscle maintenance and growth (Sandri
modulate both GH secretion and action (Leung et al., 2004). This et al., 2013; Schiaffino et al., 2013).
effect of estrogen may be due to a combination of a reduction
of somatostatin’s inhibitory tone, amplification of endogenous
GHRH levels or its pituitary actions, and activation of additional IGF-1, EXERCISE, AND EFFECTS ON
mechanisms; e.g., estrogen stimulates GH secretion by decreasing MUSCLE METABOLISM
liver secretion of IGF-1, resulting in stimulation of the pituitary to
synthesize and secrete GH (Cook, 2004; Nakamura and Aizawa, As previously discussed, GH acts through its receptor; however,
2017). many effects linked to RE and muscle growth are believed to act
The physiological relevance of increases in GH levels after RE indirectly through an increase in hepatic release of IGF-1. IGF-1
may be increases in protein synthesis and its ability to aid in can also promote muscle growth in the absence of GH; and unlike
muscle repair (Gibney et al., 2007; Liu et al., 2008) and impact GH, IGF-1 is critical for intrauterine growth (Velloso, 2008). A
on muscle mass (Hermansen et al., 2017), without any impact on liver-specific knockout mouse exhibited some postnatal growth
muscle function (Hermansen et al., 2017). It was reported that reduction, but not as severe as with global IGF knockout (Baker
there is a correlation between acute RE-induced GH increases et al., 1993; Tahimic et al., 2013). Bikle et al. also showed muscle

atrophy was more pronounced after ablation of muscle IGF-1 of circulating levels of IGF-1 (Coleman et al., 1995). Therefore,
production than when hepatic IGF-1 production was suppressed serum levels of IGF-1 (resting levels or acutely after RE) may not
(Bikle et al., 2015); exhibiting circulating levels of IGF-1 (i.e., be a good reflection of local effects of IGF-1 (Bartke and Darcy,
endocrine factor) do not effect overall growth responses (Ohlsson 2017; Van Nieuwpoort et al., 2018), especially in those tissues
et al., 2000; Velloso, 2008). This implies that locally produced, that have capabilities of producing the hormone themselves,
autocrine/paracrine IGF-1 plays an important role in both pre- such as skeletal muscle (Barclay et al., 2019). Indeed, circulating
and postnatal growth. The local production of IGF-1 is controlled IGF-1 levels have even been shown to decrease during periods
primarily by GH and other hormones (e.g., parathyroid and of active muscle building, likely due to a redistribution of
thyroid hormones) (Bikle et al., 2015); suggesting GH’s effect IGF-1 from the circulation into the muscle (Arnarson et al.,
on growth may be mediated in part via increased local IGF- 2015). If such a sequestration of IGF-1 into muscle increases
1 production and/or action. These results indicated GH has during RE (with a decrease in cellular GH receptors), it might
local effects that may be independent of increased levels of the occur as a result of reduced GH-induced hepatic production
circulating IGF-I (Ohlsson et al., 2009). However, a role for (Eliakim et al., 1998) and it may be speculated that the effect
circulating liver-derived IGF-I could not be excluded. Reflecting would be more pronounced in individuals experiencing greater
this, it has been reported that IGF-1 levels are associated with activation of intracellular muscle signaling and subsequent
improvements in handgrip strength and physical performance muscle hypertrophy and performance (Velloso, 2008; Arnarson
as well as life-span (Birnie et al., 2012; Yusuf et al., 2020); in et al., 2015; Morton et al., 2016). This suggests that intrinsic
addition, higher circulating IGF-1 has been linked with increases secretion (i.e. autocrine) of muscle IGF-1, beside circulating IGF-
in MPS, muscle free fatty acid utilization, and improvements 1, may be a determinant for switching on anabolic pathways
insulin sensitivity (Kraemer et al., 2017), which may explain (Morton et al., 2018) and fusion of satellite cells (Velloso, 2008).
its often linked importance in exercise training adaptations. Given the fairly short half-life of unbound IGF-1 in serum
Systemic IGF-1 levels are rapidly increased in humans in (i.e., 5–10 min), binding to an IGF binding protein (IGFBP-
response to RE from ∼45 (resting levels) to 65 nM (immediately 3 is the most prevalent) in serum or in ECM increases IGF-
after RE) (Schwarz et al., 1996; West et al., 2009; Ogasawara et al., 1 half-life to around 25 min (Allard and Duan, 2018). In
2013) and return to baseline levels ∼30 min after RE (Kraemer addition, IGFBPs are important in potentiating IGF-1 anabolic
et al., 2017), which may play an important role for exercise- signaling. The potentiating action occurs when the IGF-1-IGFBP
induced hypertrophy (Kido et al., 2016), neurogenesis (Trejo binds to the target cell’s ECM components, which results in
et al., 2001), and improved muscle strength with RET (Bjersing activation of IGF-1 receptor (IGFR) and then IGF-1 enters the
et al., 2017) by improving translational efficiency (Schiaffino cell and triggers phosphoinositide 3-kinase (P13-K) to generate
and Mammucari, 2011) and satellite cell proliferation (Velloso, phosphatidylinositol-bisphosphate (PIP2) (Pinedo-Villanueva
2008) in muscle and in the central nervous system (CNS) et al., 2019), leading to the production of phosphatidylinositol
(Mainardi et al., 2015). GH-induced IGF-1 released from the 3,4,5-trisphosphate (PIP3) (O’Neill et al., 2015). PIP3 is then free
liver in response to RE is involved in two negative feedback to bind to phosphoinositide-dependent kinase-1 (PDK1) which
loops. One directly affects the somatotropic cells of the anterior activates the Akt-mTORC1 pathway (Schiaffino and Mammucari,
pituitary, itself inhibiting further release of GH, whilst the other 2011) promoting ribosomal biogenesis and translation to permit
affects GH releasing hormone and somatostatin release from the increases in MPS and the formation myofibrillar proteins, which
hypothalamus to reduce the secretion of GH. Repeated bouts of allows muscle mass growth (Menon et al., 2014; Wen et al.,
RE resulted in an exercise-induced GH response to each acute 2016) (Figure 1). Similar to GH, IGF-1 alone stimulates the
exercise episode, thereby increasing the 24-h secretion of GH IRS1/Akt (Costoya et al., 1999; Consitt et al., 2017) and mitogen-
and then IGF-1. Thus, exercise counters negative feedback and activated protein kinase (MAPK) pathways which are thought
so IGF-1 secretion is maintained or increased (Godfrey et al., to be main pathways contributing to GH/IGF-1-induced muscle
2003). Further, to what we already showed [i.e., testosterone hypertrophy (Consitt et al., 2017). Also, RE-induced IGF1-Akt
increased IGF-1 gene expression during RET (Gharahdaghi et al., activation phosphorylates AS160 (Akt substrate of 160 kDa)
2019)], both testosterone and estrogen blunted IGF-I feedback- resulting in enhanced GLUT4 translocation and glucose uptake,
dependent inhibition of GH secretion (Veldhuis et al., 2004, reflecting the mediator role of IGF-1 in glycaemic control via
2005); and as it was reported in prepubertal boys, lead to insulin-IGF-1-Akt pathway activation in muscle (Kido et al.,
increase in GH and then IGF-1 levels; which in turn exhibit 2016). Taken together, IGF-1 signaling, including prolonged Akt
the further and indirect anabolic links between androgens and and AS160 phosphorylation, may be a specific signal response
muscle growth (Mauras et al., 2003). Like testosterone levels, to acute RE; which transduces mechanical signals leading to
older adults experience a lower basal level of IGF-1 (the so- anabolic responses and allow IGF-1 signaling to stimulate the
called somatopause which refers to the diminishment of the competing processes of muscle cellular growth.
GH-IGF-1 system) which attenuates post-RE levels of IGF-1
(Kraemer et al., 1999). However, RE increases IGF-1 mRNA
and IGF-1 peptide production in younger adults which result CONCLUSION
in increases in muscle DNA and protein content (Adams and
Haddad, 1996). Increased expression of IGF-1 in muscle leads RE-induced increases in key endogenous steroid and peptide
to muscle hypertrophy in mice; which is independent of effects hormone responses are likely to be an integral part of the

integrated response to acute exercise and exercise-induced hierarchical roles of the key anabolic hormones/peptides in
muscle growth. The combined effects of RE and RE-induced regulating muscle growth in adults, in particular after RE, and
androgen release lead to upregulation of anabolic signaling to elucidate sex differences and their mechanisms.
pathways which likely augment net protein accretion and
hypertrophy. However, the anabolic effects of RE-induced AUTHOR CONTRIBUTIONS
GH release act indirectly via stimulation of hepatic-IGF-1
production; in turn resulting in the activation of anabolic NG, DW, and PA drafted the manuscript and BP, NS, KS, DW,
signaling pathways, and muscle growth and maintenance. and PA helped in literature search and edited the manuscript. All
Lower levels of these anabolic hormones in older adults authors approved the submitted version.
induces anabolic resistance during RE which may partially
explain their low sensitivity to a given anabolic stimulus. FUNDING
Hormonal patterns are obviously physiologically distinct in
females and males, complicating true clarity of the isolated effects This research was supported by the MRC-Versus Arthritis
e.g., of the sex hormones (higher testosterone levels may play Center for Musculoskeletal Aging Research [grant numbers
an important role for the adaption to RET in men; whereas in MR/R502364/1, MR/P021220/1] and the National Institute
premenopausal women, estrogen may enhance the sensitivity to for Health Research (NIHR) Nottingham Biomedical
anabolic stimuli). Further studies are required to isolate clear Research Center.
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