Metabolism 154 (2024) 155816
Contents lists available at ScienceDirect
Metabolism
journal homepage: www.journals.elsevier.com/metabolism
Editorial
Are we underestimating the potential of neuroactive drugs to augment neuromotor function
in sarcopenia?
A R T I C L E I N F O
Keywords
Motor neuron
Persistent inward currents
Neuromodulation
Physical function
Aging
Sarcopenia is a skeletal muscle disease characterised by exacerbated
loss of muscle mass, strength, and/or impaired function with aging and/
or disease [2–7]. Historically, the term “sarcopenia” stems from the
Greek words ‘sarx’, for ‘flesh’, and ‘penia’, for ‘loss’, and thus was used
to describe age-related loss of muscle mass [8,9]. However, growing
recognition that low muscle strength and/or impaired physical function
are independent (and often better) predictors of mobility limitations,
falls, fractures, and many other health outcomes than muscle mass alone
has led to the current multi-dimensional definition of sarcopenia
[10–14]. Despite this, many therapeutic pharmacological development
(e.g., medications targeting myostatin/activin pathways, growth
hormone/insulin-like growth factor 1 pathways, mitochondrial
biogenesis, and steroid hormones) to counteract sarcopenia have mostly
targeted muscle wasting, as highlighted by the comprehensive review by
Rolland et al. [1]. While some of these pharmacological agents have
been effective in attenuating losses in muscle mass and to a lesser extent
muscle strength, these benefits have not translated into any improve­
ments in physical function [1]. This, along with the fact that effective
interventions (i.e. resistance exercise) can improve physical function
with little or no muscle hypertrophy, raises the question of whether
pharmacotherapies should target aspects of muscle activation/control
beyond mass itself. One important area that is underappreciated in the
field of sarcopenia is the impact of age-related nervous system impair­
ments [15], especially impairments affecting spinal motoneurons, which
play a key role in controlling muscle contractions (force generation) and
physical function.
Muscle contractions are directly dependent on the ability of the
nervous system to activate muscle fibres. The control of force produced
by the muscle is a product of the number of recruited motor units and the
frequency at which their motoneurons discharge action potentials. In
other words, to attain higher motor unit force levels, the discharge
frequency of motoneurons must be increased accordingly. This is
controlled by: i) net excitatory input from the central nervous system to
https://doi.org/10.1016/j.metabol.2024.155816
Received 17 January 2024; Accepted 9 February 2024
Available online 15 February 2024
0026-0495/© 2024 Elsevier Inc. All rights reserved.
the motoneurons, and ii) the intrinsic capacity that motoneurons have of
integrating and modulating excitatory synaptic input to evoke an
appropriate motoneuron (and thus motor unit) discharging output [16].
A remarkable feature of motoneurons is their ability to act as an
“amplification system,” increasing the received net excitatory input to
much higher levels of output, allowing the motor unit to discharge at
higher frequencies [17]. This input-output gain system within the mo­
toneurons is facilitated by the generation of persistent inward currents
(PICs) [18]. PICs are intrinsic depolarising currents in motoneurons
generated by voltage-gated calcium and sodium channels located at the
somatodendritic compartment [19]. PICs increase cell excitability,
accelerating, amplifying, and prolonging the output activity of moto­
neurons for a given synaptic input [19]. Simulation experiments suggest
motoneuron output can be amplified by as much as five-fold by PICs
[17], and without it, motoneurons would not be able to achieve the
discharging frequencies necessary for the muscle to produce more than
40 % of maximal force, which is required for a variety of daily living
tasks [20]. Several lines of evidence suggest that PIC modulation works
in balance with task demand, adjusting motoneuron firing frequency
based on the level of force required to complete the task [17,21–23].
Therefore, this intrinsic property of motoneurons (i.e., PICs) is essential
for normal motor behaviour and production of fast and higher levels of
force.
The human neuromotor system is known to experience substantial
deterioration over the lifespan [15], and this is no different from a
motoneuron perspective. In addition to structural damage, motoneuron
death, and motor unit remodelling [24], the intrinsic ability of moto­
neurons to generate PICs is also reduced [25]. The PIC contribution to
motoneuron firing in humans can be estimated by analysing the firing
behaviour of motor unit pairs using the Paired Motor Unit Analysis
[26,27]. This assessment can be carried out non-invasively in humans by
integrating advanced myoelectrical signal acquisition techniques, such
as High-Density Electromyography, and employing algorithms to
Editorial Metabolism 154 (2024) 155816

Fig. 1. Persistent inward currents (PICs) allow motoneurons to amplify their firing frequency output for a given excitatory input, enabling them to reach the firing
frequencies necessary to produce higher levels of force and perform a variety of physical tasks. Age-related reductions of serotonin (5-HT) and noradrenaline (NA)
input onto motoneurons attenuate their ability to generate PICs, thus slowing down their firing frequencies. Repurposing or developing novel drugs targeting
restoration of the 5-HT and NA systems in sarcopenic individuals holds promise for improving motoneuronal function, hence enhancing physical function.

decompose these signals into individual motor unit firing trains [28,29].
Applying these methods, recent cross-sectional human studies suggest
large magnitude reductions in PIC contribution to motoneuron firing in
older individuals [25], in all the muscles tested to date including the
tibialis anterior, soleus [30,31], vastus lateralis [32], biceps brachii, and
triceps brachii [33]. Weaker PICs contribute to the observed reduction in
the firing frequency modulation observed in aged motoneurons [34]. A
recent study provided initial evidence that partially restoring PIC
contribution to motoneuron firing (with no changes in muscle mass) in
older adults following 6 weeks of resistance training was associated with
improvements in muscle strength and physical function [35]. Thus, it is
likely that motoneuronal PICs play an important role in force production
capacity and physical function/motor control losses, and that improving
PIC function is a promising therapeutic target to improve functional
capacity independent of muscle hypertrophy.
Age-related declines in monoaminergic drive to motoneurons may be
one of the main mechanisms explaining age-related reductions in PIC
amplitude, as motor unit firing frequencies, and thus PICs, are strongly
influenced by serotonergic and noradrenergic release [36]. There is
evidence of reductions in serotonin (5-hydroxytryptamine, 5-HT) and
noradrenaline (NA) concentrations in the brains of aged rats [37]. In
humans, deterioration of locus coeruleus structural integrity [38] and
decline in neuromelanin content in noradrenergic neurones originating
from the locus coeruleus [39] may reflect declines in NA secretion and
projections to the spinal cord in older adults. Degeneration of seroto­
nergic axons projecting to the ventral horn of the lumbar spinal cord,
where motoneurons innervating lower limb muscles originate, has also
been observed [40], impacting serotonergic drive onto motoneurons.
Moreover, reduced 5-HT and NA receptor sensitivities on the
motoneurons, may further compromise the already diminished mono­
aminergic drive onto motoneurons. This, in turn, could impair the
generation and subsequent modulation of PICs in this population. The
potential of altering neuromodulation levels, particularly 5-HT and NA,
through pharmacological interventions could be promising in address­
ing age-related declines in monoaminergic drive to motoneurons.
The impact of pharmacological modulation on 5-HT and NA release
or receptor sensitivity in relation to PICs and motor output has been
extensively investigated across both animal and human studies [41].
Recent human studies demonstrate that Selective Serotonin Reuptake
Inhibitors (SSRIs) such as paroxetine [42,43] and NA stimulants,
including amphetamine and reboxetine [44,45] elicit slight increases in
unfatigued maximal force and/or voluntary activation in young in­
dividuals presumed to have normal monoaminergic function. This sug­
gests a potential role for increased PIC facilitation, supporting the notion
that administering SSRIs and NA stimulants may further enhance
strength in individuals with compromised 5-HT and NA function, such as
older adults, especially sarcopenic individuals. The facilitatory effects of
5-HT on PICs appear to be 5-HT2 receptor-mediated [41]. Human
studies reveal that blocking the 5-HT2 receptor diminishes PIC contri­
bution to motoneuron firing [46,47]. However, the absence of known
selective agonists for 5-HT2 receptors available for human use may limit
immediate therapeutic approaches. SSRIs, such as Citalopram [47], may
be employed to enhance 5-HT release and promote 5-HT2 activation.
Other promising targets for drug development based on animal experi­
ments include alpha 1 agonist, alpha 2 antagonist, and amphetamine
prodrugs. Briefly, alpha 1 agonist directly activate alpha 1 receptors on
motoneurons, alpha 2 antagonists block the negative feedback mecha­
nism that usually reduces NA release such that more NA is available in

2
Editorial
synapses, and amphetamine prodrugs (e.g., lisdexamfetamine/dex­
amphetamine) because of their influence in increasing NA availability. It
is worth noting that repurposed drugs have systemic administration and
may be insufficient in producing a substantial enhancement of the 5-HT
and/or NA transmission precisely at the spinal cord/motoneuron,
specificity that could be considered for novel drugs development. While
theoretically, the use of 5-HT and NA drugs may hold promise for
improvement of muscular strength and function, current evidence is
based on preclinical experiments in animal models or by repurposing
drugs in healthy human experiments. Therefore, further clinical trials
involving sarcopenic individuals are necessary to determine the efficacy
and long-term effects of such treatments before widespread adoption
can be recommended.
Potential adverse effects must be considered when developing or
repurposing and testing these types of neuroactive systemic drugs in
older and sarcopenic individuals. Heightened 5-HT levels induced by
certain drugs (e.g., buspirone [48]) have been associated with the
activation of inhibitory 5-HT1 receptors on the axon initial segment,
leading to reduced motoneuron excitability. SSRIs and NA stimulants
have been linked to increased central fatigue and perceptions of fatigue
[42,43,49,50], particularly during activities involving repeated or sus­
tained physical exertion. Notably, these studies showing neuromuscular
fatiguing effects were conducted in young healthy individuals with
normal monoaminergic function. It remains unclear if restoring 5-HT
and NA to normal levels in sarcopenic individuals would be sufficient
to reach detrimental levels associated with elevated fatigue during
movements requiring sustained exertion. Systemic adverse effects must
also be considered. For instance, amphetamine prodrugs could elevate
cardiovascular risk, particularly in individuals with hypertension and
atherosclerosis [51], conditions more common among the elderly. SSRIs
may initially affect appetite, potentially exacerbating weight/muscle
mass loss in those with sarcopenia [52], or induce dizziness and
drowsiness, which could be concerning in a population at elevated risk
of falls [53]. Nevertheless, side effects associated with SSRIs are ex­
pected to ameliorate with continued use over time. Additional research,
particularly in the context of sarcopenia, is essential to elucidate the
risk-benefit ratio of this variety of pharmacological interventions.
In summary, current evidence suggests that pharmacological in­
terventions targeting the monoaminergic system can enhance moto­
neuronal neuromodulation and PIC contribution to motoneuron firing,
ultimately improving muscular strength and physical function in
humans. Thus, the development of novel drugs, or repurposing available
pharmacotherapies, targeting 5-HT and NA systems holds potential to be
tested in animal models and clinical trials (Phases 1 and 2) in older and
sarcopenic populations (Fig. 1). These drugs may mitigate physical im­
pairments independently and could also work synergistically to optimise
the effects of other pharmacotherapies focusing on muscle, as well as
non-pharmacological strategies including exercise and nutrition in­
terventions, which could be explored in Phase 3 trials.
Abbreviations
PIC Persistent Inward Current
5-HT 5-hydroxytryptamine (Serotonin)
NA Noradrenaline
SSRIs Selective Serotonin Reuptake Inhibitors
CRediT authorship contribution statement
Lucas B.R. Orssatto: Writing – review & editing, Writing – original
draft, Conceptualization. Jacob R. Thorstensen: Writing – review &
editing, Writing – original draft, Conceptualization. David Scott:
Writing – review & editing, Writing – original draft. Robin M. Daly:
Writing – review & editing, Writing – original draft, Conceptualization.
3
Metabolism 154 (2024) 155816
Declaration of competing interest
The authors declare that they have no competing interests.
Acknowledgments
LBRO is funded by an Alfred Deakin Postdoctoral Research Fellow­
ship within the Institute for Physical Activity and Nutrition (IPAN) at
Deakin University.
DS is supported by a National Health and Medical Research Council
Investigator Grant (GNT1174886).
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Lucas B.R. Orssattoa,*, Jacob R. Thorstensenb,c, David Scotta,d, Robin
M. Dalya
a
Institute for Physical Activity and Nutrition (IPAN), School of Exercise and
Nutrition Sciences, Faculty of Health, Deakin University, Geelong, Australia
b
Faculty of Health Sciences & Medicine, Bond University, Gold Coast,
Australia
c
School of Biomedical Sciences, Faculty of Medicine, The University of
Queensland, Brisbane, Australia
d
School of Clinical Sciences at Monash Health, Monash University, Clayton,
Australia
*
Corresponding author.
E-mail address: lucas.orssatto@deakin.edu.au (L.B.R. Orssatto).