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Advanced Neurology A novel approach to mitigate muscle atrophy in GBS

but differ sufficiently to induce a pathological immune 2.1.2. Disuse atrophy
response . In the specific example of C. jejuni, the People with GBS often experience prolonged periods of
[19]
most cited infection associated with the onset of GBS, in relative inactivity due to the lower limb weakness/paresis
>99% of infections there is a normal immune response and respiratory insufficiency, necessitating mechanical
[20]
against the bacteria, without damage to the host . In ventilation . Prolonged periods of muscle disuse results
[1]
the rare cases that molecular mimicry does occur, there in significant loss of muscle protein, muscle wasting,
is a formation of autoantibodies which are sensitized and loss of strength . Studies in intensive care unit
[32]
to specific gangliosides found in high concentration on patients demonstrated mechanical ventilation to cause the
peripheral nerve membranes , eventually leading to diaphragm to undergo atrophy at a rate of approximately
[21]
the onset of GBS through pathological immune response 6%–7.5% per day [33,34] . Many animal models have been used
to self-structures . The type of preceding infection and to study the mechanism of disuse atrophy, which is due to
[20]
the specificity of the antiganglioside antibodies can help both a decrease in muscle protein synthesis and an increase
to determine the GBS type and course of disease . Of in proteolysis; a pro-catabolic state within specific muscles
[22]
note, AIDP has been associated with antibodies against rather than systemically . There are two genes that have
[32]
GD1b and LM1 gangliosides found within the membranes been repeatedly shown to be upregulated in disuse atrophy,
of the myelin sheaths . Depending on the extent of muscle RING finger 1 (MuRF-1) and muscle atrophy
[23]
demyelination or axonal loss, this can lead to a disrupted F-box (MAFbx), both of which encode muscle-specific
neurotransmission, including conduction block, resulting E3 ubiquitin ligases and have a central role in ubiquitin-
in weakness or paresis . Prolonged immobilization proteasome-mediated protein breakdown . Alternatively,
[24]
[35]
and neurotransmission failure have both been shown to caspase-3 activation can be promoted through the release
independently result in loss of muscle mass, in the form of of mitochondrial cytochrome c and a high Bax: BCL-2
neurogenic or disuse atrophy [25,26] . ratios . These mechanisms are summarized in Figure 1A
[32]
(created using PowerPoint, Microsoft 365). Given that
2.1. Muscle atrophy in GBS detailed exposition of these mechanisms are quite complex,
Secondary to denervation, immobilization and overall they remain outside the scope of this review but can be
catabolic state, GBS often develop muscle atrophy . This found elsewhere [32,35] .
[10]
atrophy, and the resultant motor dysfunction, is likely a key Kondo et al. was the first to reveal that atrophy
contributor to the symptoms of long-term morbidity and secondary to skeletal muscle immobilization is associated
disability within the chronic GBS population. This section with oxidative injury . This buildup of reactive oxygen
[36]
will briefly review three potential mechanisms for muscle species, and subsequent increased oxidative stress levels,
atrophy in the GBS patient. has been shown to induce a pro-catabolic state through
[37]
2.1.1. Pro-catabolic state the inhibition of protein synthesis and promotion
of proteolysis through the caspase-3 and ubiquitin-
In a normal homeostatic individual, there is a continual proteasome pathways, as well as direct sensitization of
balance between skeletal muscle protein synthesis and myofibrils to proteolytic breakdown . There have been
[38]
breakdown . Profound systemic stress, such as that multiple studies demonstrating various antioxidant-based
[27]
associated with critical illness (which may include severe interventions (e.g., Vitamin E and cysteine) mitigating
cases of GBS), can induce a systemic pro-catabolic state. disuse-related muscle atrophy in animal models [39-41] .
This catabolic state includes an overall decrease in anabolic
effector hormones and an upregulation of various catabolic 2.1.3. Neurogenic atrophy
pathways . The putative purpose of this overall state of In GBS, motor axon loss (Figure 2A) may occur directly
[28]
catabolism is to provide the body with free amino acids, as part of the pathophysiological disease process in
which are essential for gluconeogenesis, new protein some subtypes (e.g., AMAN) or secondary to severe
synthesis, and energy production . When prolonged, this demyelination in AIDP . Loss of motor axons causes
[29]
[3]
pro-catabolic state can lead to substantial muscle wasting muscle denervation, which leads to muscle cell death
and weakness . Factors that promote a pro-catabolic and fibrosis in the absence of collateral reinnervation, in
[30]
state include pro-inflammatory cytokines, prostaglandins, a process termed neurogenic atrophy . Loss of motor
[42]
glucocorticoids, catecholamine, and growth hormone, in innervation triggers cellular signals within denervated
addition to a decline in anabolic agents, such as insulin- myofibers producing a localized pro-catabolic state .
[42]
like growth factor-1 . For more detailed review of the Foundational studies have shown denervated myofibers to
[30]
physiology underlying the pro-catabolic state induced by have generally increased levels of mRNA transcription as
[43]
critical illness, please see Cheung et al. . well as increased polyubiquitin levels , ubiquitin-protein
[44]
[31]
Volume 2 Issue 2 (2023) 3 https://doi.org/10.36922/an.280