A Review on the Mechanisms of Stroke-Induced Muscle Atrophy

Abstract

This comprehensive review elucidates the intricate, multifactorial pathophysiology underpinning post-stroke skeletal muscle atrophy, a detrimental complication impacting patient outcomes. Post-stroke complications including dysphagia, malabsorption, and inadequate protein intake precipitate a catabolic state, exacerbating muscle wasting. The dearth of essential amino acids perpetuates proteolysis over protein synthesis, highlighting the importance of nutritional interventions. Immobility-induced disuse atrophy and dysregulation of anabolic pathways, notably IGF/Akt/PI3K, favor proteolysis, disrupting muscle protein homeostasis. Proteolytic systems including the ubiquitin-proteasome pathway and autophagy play central roles. Moreover, transcriptomic alterations, insulin resistance, autonomic dysregulation, inflammation, oxidative stress, and dysregulated microRNAs contribute to reduced muscle mass post-stroke. Notably, matrix metalloproteinases’ (MMPs) implication unveils potential therapeutic avenues via MMP inhibition. Unraveling this complex pathophysiological interplay is crucial for developing multi-modal interventions to manage post-stroke muscle atrophy effectively.

1. Introduction

Strokes are profound and often life-threatening neurological events that prominently contribute to global morbidity and mortality. The global prevalence of strokes is staggering. According to the World Health Organization (WHO), stroke accounts for an estimated 13.7 million new cases each year, with mortality rates surpassing five million annually. Stroke is the second-leading cause of death globally, accounting for an estimated 11.9% of all deaths in 2019 [1], trailing only behind ischemic heart disease. In 2019, the global age-standardized incidence rate of stroke was 128 per 100,000 population, with the highest rates in sub-Saharan Africa and South Asia. Beyond mortality, strokes leave a profound mark on survivors, often resulting in significant physical, cognitive, and emotional impairments. Mobility limitations, communication difficulties, and altered cognitive function are among the many challenges that stroke survivors, and their families, grapple with, amplifying the burden of stroke-induced disabilities.

There are two primary types of strokes: ischemic and hemorrhagic. Ischemic strokes, constituting more than 85% of all cases [2], occur when a blood clot obstructs a blood vessel supplying the brain. Hemorrhagic strokes, on the other hand [3], emerge as a rupture of a blood vessel, leading to bleeding within or around the brain. Both types result in compromised oxygen and nutrient supply to the brain tissue, leading to rapid and potentially irreversible damage.

Post-stroke patients often experience hemiparesis, muscle weakness/partial paralysis on one side of the body that can affect the arms, legs, and facial muscles [4], and muscle atrophy [5]. Muscle atrophy refers to the loss of muscle mass and can result from a combination of factors including disuse, inflammation, and altered neural signaling. Both ischemic and hemorrhagic strokes can contribute to muscle atrophy, although the mechanisms through which they do so may differ. In ischemic stroke, a lack of oxygen and nutrients to the affected brain region can trigger a cascade of events that affect the brain tissue as well as the neural connection between the brain and muscles. Following an ischemic stroke, patients often experience muscle weakness, paralysis, and decreased motor control due to damage in the brain regions responsible for motor function. The resulting immobility and reduced use of affected muscles can lead to disuse atrophy, where the lack of muscle contractions and mechanical stress contributes to muscle wasting. Changes in motor control and coordination can also occur through neural plasticity, the brain’s ability to rewire itself. In some cases, this rewiring can negatively impact muscle activation and coordination, leading to imbalanced muscle loading and subsequent atrophy. Hemorrhagic strokes lead to bleeding within or around the brain, causing direct damage to the brain tissue and neural pathways, which can have a ripple effect on muscle health. This bleeding effect also triggers inflammation in the brain and surrounding tissues, leading to the release of cytokines and other inflammatory molecules the affect neural signaling and contribute to muscle protein degradation.

Considering the alarming statistics and far-reaching implications of stroke, understanding and addressing stroke-induced muscle atrophy stand as an urgent priority for global health. By delving into the dimensions of this multifaceted condition, we can collectively endeavor to mitigate effects, alleviate the burden on healthcare systems, and ultimately enhance the well-being of those affected by this complex health challenge. This review focuses on the mechanisms and factors that lead to muscle atrophy as a result of stroke. This paper delves into three major protein degradation pathways associated with stroke-induced muscle atrophy and will also explore the interplay between insulin resistance and stroke-induced muscle atrophy. Additionally, given muscle atrophy after a stroke is closely linked to central nervous system changes, denervation, altered motor unit activation, and morphological changes in the central nervous system will be discussed. Furthermore, this review will cover how reactive oxygen species and the NF-kB transcription factor play crucial roles in inflammatory response that contribute to muscle weakness. Finally, MicroRNAs (miRNAs) and Matrix Metalloproteinases (MMPs) will be briefly discussed in the context of muscle atrophy following a stroke.

2. Protein degradation pathways associated with stroke-induced atrophy

2.1 Diet- and disuse-associated protein degradation

Stroke survivors may experience difficulties eating secondary to weakness in swallowing muscles and/or have impaired nutrient absorption, leading to inadequate protein intake and malnutrition [6]. The lack of essential amino acids, the building blocks of proteins, further exacerbates muscle protein breakdown. Randomized-controlled studies have shown that branched-chain amino acid (BCAA) supplementation can ameliorate muscle wasting after stroke, further demonstrating the important role of protein synthesis in stroke-induced sarcopenia [7, 8].

Following a stroke, patients often experience immobility due to motor impairments or being bedridden during the acute phase of recovery. Retrospective studies have shown that more than 4 in 10 stroke patients report physical activity following their cerebrovascular accident (CVA) [9]. Muscle disuse related to physical inactivity has been linked to muscle atrophy in both healthy and critically ill subjects [10, 11]. Therefore, it seems likely that high rates of muscle disuse in stroke patients contribute to the prevalence of accelerated protein degradation and subsequent muscle wasting.

Stroke-induced changes in signaling pathways involved in muscle protein synthesis and breakdown can lead to an imbalance favoring protein degradation over synthesis. Skeletal muscle mass reflects a dynamic balance between hypertrophic and atrophic signaling pathways. Muscle atrophy can occur through downregulated hypertrophic signaling and/or upregulated atrophic signaling. After a cerebral ischemic episode, patients exhibit hypoactive hypertrophic pathways and hyperactive atrophic pathways. These pathways are detailed below.

2.2 IGF/Akt/PI3K pathway

The IGF/Akt/PI3K pathway plays a pivotal role in regulating cell growth, survival, and metabolism. Activation of this pathway, typically initiated by insulin-like growth factor-1 (IGF-1), triggers a signaling cascade involving phosphatidylinositol-3 kinase (PI3K) and Akt, leading to downstream effects such as protein synthesis, inhibition of apoptosis, and metabolic regulation [12]. In the context of muscle physiology, this pathway is critical for muscle growth and maintenance (Figure 1). Its activation promotes protein synthesis and suppresses muscle atrophy by inhibiting the activity of FOXO transcription factors that induce muscle-specific ubiquitin ligases responsible for protein degradation [12]. Increased activity of the IGF/Akt/PI3K has been shown to promote skeletal muscle in both rodent and human models [13, 14]. Conversely, in conditions of muscle atrophy, such as disuse or disease, dysregulation of the IGF/Akt/PI3K pathway contributes to muscle wasting [12, 15, 16].

Figure 1.

Molecular pathways related to stroke-induced muscle atrophy. Stroke-induced muscle atrophy involves complex interplays of various pathways. The ubiquitin-proteasome system plays a central role in skeletal muscle atrophy, marked by increased protein degradation. Dysregulated UPS is implicated in stroke-induced sarcopenia, with studies in rodents and humans showing increased proteasome signaling and catabolic proteins in paretic muscles. Therapies reducing UPS activity have demonstrated efficacy in limiting muscle atrophy post-stroke. The autophagy-lysosome pathway, responsible for protein and organelle degradation, is upregulated after stroke. Hyperactive autophagy contributes to muscle atrophy, with murine models showing increased activity post-ischemia. Restoring regulators like SirT1 reversed muscle loss, highlighting potential therapeutic targets. Insulin resistance emerges post-stroke, affecting muscle mass and contributing to sarcopenia. Connections between type 2 diabetes, insulin resistance, and stroke highlight a need for further exploration. Interventions such as resistive training show promise in reducing insulin resistance and improving insulin sensitivity, suggesting a potential link between diabetes and muscle atrophy in chronic stroke patients. Autonomic dysregulation, marked by sympathetic overactivation, correlates with muscle atrophy severity post-stroke. Catecholamine surge triggers proinflammatory responses, emphasizing the intricate relationship between autonomic and inflammatory pathways. Hepatic dysfunction following stroke adds another layer, with potential connections to muscle atrophy. The liver releases factors like beta-hydroxybutyrate, explored for its neuroprotective and muscle-preserving effects. The IGF/Akt/PI3K pathway, crucial for cell growth and muscle maintenance, is disrupted in stroke, leading to downregulation of hypertrophic pathways and activation of atrophic pathways. Restoring IGF/Akt/PI3K activity holds promise for mitigating stroke-induced muscle atrophy. Figure made in BioRender.com.

The IGF/AKT/PI3K pathway is intricately linked to stroke-induced muscle atrophy, also known as sarcopenia or muscle wasting. In both human and rodent models of cerebral ischemia, altered Akt signaling has been identified as a significant factor. For instance, permanent occlusion of the left distal medial cerebral artery (MCA) in rodents results in reduced Akt kinase activity, thereby affecting downstream signaling pathways [17]. This alteration induces global and muscle-specific downregulation of Akt/PI3K pathways, leading to muscle wasting [18].

Transcriptome-level changes also play a pivotal role in this relationship. Cerebral ischemia leads to the decreased expression of multiple genes associated with the IGF/Akt/PI3K signaling cascade, including IGF1, PIK3ap1, PIK3cg, and TLR2 [19]. This downregulation further contributes to the reduction in muscle mass following cerebral ischemia [20].

Hypoactive IGF/Akt/PI3K kinase activity in human and rodent models has been linked to decreased muscle mass through the limitation of hypertrophic pathways and stimulation of atrophic pathways [12, 14]. Therefore, interventions aimed at increasing IGF/Akt/PI3K activity have the potential to ameliorate stroke-induced muscle atrophy and sarcopenia [21].

2.3 Ubiquitin-proteosome system

Ubiquitin-proteasome signaling plays a crucial role in skeletal muscle atrophy, a condition characterized by muscle loss due to increased protein degradation (Figure 1). The ubiquitin proteasome system (UPS) is a central pathway responsible for protein degradation in muscle cells during atrophy [22]. UPS activation involves tagging proteins with ubiquitin molecules, which targets them for proteasomal degradation [23]. In atrophying skeletal muscle, the ubiquitination process serves as a signal for protein turnover, leading to rapid muscle mass loss [24]. Multiple factors contribute to UPS-mediated muscle atrophy. Inflammation-induced muscle atrophy involves proinflammatory cytokines and acute phase response proteins, with their associated signaling pathways triggering UPS activation [22]. This process ultimately results in the degradation of muscle proteins and subsequent muscle wasting.

Given its prominent role in protein degradation, it is unsurprising that the dysregulated ubiquitin proteosome system has been implicated in mediating stroke-induced sarcopenia. Rodents with cerebral ischemia-induced atrophy in the tibialis anterior, quadriceps, and soleus exhibit a concomitant increase in MurF1 and MAFbx mRNA throughout the paretic muscle [20]. Cerebral ischemia also induces upregulated proteosome signaling and increased expression of catabolic proteins such as caspase-3 and caspase-6 [25]. In humans, therapies that reduce ubiquitin-proteosome activity have been shown to limit muscle atrophy in stroke patients.

2.4 Autophagy lysosome system

In the context of muscle atrophy, autophagy refers to a lysosomal pathway that degrades and recycles proteins and organelles in the cytoplasm [26]. The autophagy-lysosome pathway is upregulated in a number of conditions associated with muscle wasting including cancer, caloric restriction, sepsis, and cirrhosis [27]. Given the role of the autophagy-lysosome pathway in degrading proteins, hyperactive autophagic signaling leads to muscle atrophy [28, 29, 30]. Inhibition of autophagy can also disrupt myofiber homeostasis and therefore cause skeletal muscle atrophy [31, 32, 33, 34].

Cerebral ischemia and the post-stroke inflammatory sequelae, discussed later in this review, upregulate autophagic signaling [35]. Murine model studies suggest that hyperactive autophagy-lysosome pathway activity may contribute to stroke-induced muscle atrophy. Following cerebral ischemia, inhibitory phosphorylation of proteins that are critical for autophagy including Ulk1 is decreased, potentially leading to over activation [20]. Additional studies have demonstrated that the expression of SirT1, a key regulator of proteins involved in autophagic signaling, is dramatically repressed following cerebral ischemia [36]. Notably, reduced expression of this regulator correlated with skeletal muscle loss in ischemic rats. Restoring SirT1 function reversed skeletal muscle loss in a murine model of stroke [36].

3. Endocrine and metabolic signaling associated with stroke-induced atrophy

3.1 The role of insulin resistance and its interplay with stroke

Insulin resistance (IR) is characterized by the impaired cellular response to insulin and is recognized as an independent risk factor for various stroke types (Figure 1). Stroke-related reduced morbidity contributes to changes in skeletal muscle mass, including fatty infiltration, which is associated with the emergence of insulin resistance [37]. The precise connection between insulin resistance and stroke-induced muscle atrophy is an area of ongoing investigation.

Extensive research has focused on the interplay between insulin resistance and the development of ischemic stroke. A substantial proportion of acute stroke patients exhibit abnormalities in glucose regulation, leading to extensive exploration of the connection between type 2 diabetes (T2D) and ischemic stroke [38]. T2D, characterized by chronic hyperglycemia and insulin resistance, creates a metabolic microenvironment conducive to endothelial dysfunction and platelet hyperactivation [39]. Furthermore, a study demonstrated a notable upregulation of myostatin mRNA expression in paretic muscles compared to their non-paretic counterparts among stroke survivors; specifically, the expression levels were found to be 40% higher in the affected muscle groups [40]. This increase in myostatin mRNA expression could be due to intramuscular fat accumulation, consequent to stroke, that may cause insulin resistance, and the subsequent hyperinsulinemia [41]. Although recent investigations have reported a substantial prevalence of both T2D and IR among stroke patients, the temporal relationship between stroke and diabetes and the underlying mechanisms remain ambiguous.

3.2 Persistent insulin resistance in chronic stroke recovery

Remarkably, insulin resistance persists during the chronic recovery phase following a stroke, raising questions about its role in muscle atrophy and its potential association with diabetes. Studies examining chronic stroke survivors have revealed stark differences in muscle composition between paretic and nonparetic limbs, with paretic limbs showing a significant reduction in muscle area and volume, along with an increase in intermuscular adipose tissue [40]. However, interventions have been investigated to reduce insulin resistance. A study also found that resistance training (RT) decreased mRNA expression of Sirtuin-1 (SIRT1) and increased mRNA expression of Proliferator activator receptor (PPAR)-γ coactivator (PGC-1α), regulators of insulin resistance, reducing hyperinsulinemia and improving the insulin action in chronic stroke [42]. Moreover, RT was also found to improve insulin sensitivity in chronic stroke recovery [43]. These findings suggest a linkage between skeletal muscle atrophy and diabetes in chronic stroke patients, warranting further exploration.

3.3 Autonomic dysregulation, inflammation, and their widespread effects

Dysregulation of autonomic systems exerts profound effects on various organs throughout the body. This section explores the implications of autonomic dysregulation on endocrine equilibrium and its pivotal role in driving muscle atrophy after stroke. A comprehensive understanding of the intricate interplay between autonomic dysregulation is essential for devising targeted interventions to address stroke-induced muscle atrophy.

Upon the occurrence of a stroke, a cascade of catabolic pathways is initiated within muscle tissues. Notably, this includes the phenomenon of sympathetic overactivation, which significantly contributes to the atrophy of the afflicted muscles. Importantly, the severity of brain injury exhibits a direct correlation with the extent of muscle atrophy [25]. Elevated sympathetic signaling, characterized by heightened local and systemic catecholamine levels, emerges as a central driver behind the stimulation of a global catabolic state. Crucially, heightened sympathetic activity intricately intertwines with the activation of proinflammatory cytokines, as vividly exemplified in an animal model of stroke. Here, the surge in catecholamine levels, arising from sympathetic nervous system activation, exerts influence on the splenic inflammatory response through binding with α and β adrenergic receptors [44]. This observation aligns with prior research that underscores the protective attributes of the adrenergic receptor blocker, carvedilol, in ischemic brain scenarios. This protection is marked by the attenuation of TNF-α and IL-1 expression, in conjunction with the inhibition of apoptosis in cases of focal cerebral ischemia [45]. Additionally, administration of the β-blocker propranolol or antibiotic enrofloxacin demonstrated similar results [46, 47].

Moreover, empirical data have unveiled hepatic dysfunction as a systemic consequence of stroke, concurrently shedding light on a growing recognition of the connection between liver disease and stroke-induced muscle atrophy. This is underscored by documented changes in plasma liver function tests induced by stroke, further highlighting the association between liver fibrosis and the risk of stroke [48]. Interestingly, research has revealed that a higher skeletal muscle mass possesses a protective capacity against long-term cirrhosis [49]. Additionally, the liver’s role extends beyond mere pathology; factors released by the liver, such as the neuroprotective ketone body beta-hydroxybutyrate (DBHB), have demonstrated potential in mitigating the effects of stroke [50]. Significantly, DBHB has also been explored as a therapeutic avenue to counteract muscle atrophy [51]. While these findings allude to a potential link between liver function and muscle atrophy induced by stroke, it is evident that extensive research is warranted to elucidate the intricate relationship between skeletal muscle and liver damage, including cirrhosis. This quest for understanding underscores the need for further investigation into the relationship between hepatic dysfunction and skeletal muscle atrophy, a subject deserving of more extensive scrutiny.

4. Central nervous system changes associated with stroke-induced muscle atrophy

Muscle atrophy following a stroke is primarily linked to central nervous system changes that affect motor control and neural signaling [52]. Given that strokes cause damage to specific areas of the brain, mainly the motor cortex and subcortical regions, disruptions in neural pathways that control voluntary muscle movements can result in mild weakness to paralysis. Stroke-induced central nervous system changes have been linked to reduced neural input and altered motor unit activation. Changes in motor unit activation can result in abnormal force distribution and muscle disuse, both of which contribute to atrophy. Some individuals experience muscle spasticity [53] due to increased muscle tone and involuntary muscle contractions. Spasticity can lead to reduced joint range of motion and muscle overuse, contributing to muscle atrophy. Following a stroke, the brain often undergoes cortical reorganization. Neighboring brain areas may compensate for the damaged regions, leading to changes in motor representations [54, 55]. While this can help recover some motor function, it may also lead to less efficient motor control and altered muscle activation patterns. The morphological changes in the central nervous system that occur after stroke, including neurotransmitter dysfunction, denervation, reduced synaptic plasticity, neuromuscular junction changes, and reduced synaptic density, will be further discussed with regards to leading to muscle atrophy (Figure 2).

Figure 2.

Effects of stroke on the neuromuscular and central nervous system leading to muscle atrophy. Muscle atrophy following a stroke is intricately linked to central nervous system changes that disrupt motor control and neural signaling. Stroke-induced damage to the motor cortex and subcortical regions leads to reduced neural input, altered motor unit activation, and, in some cases, muscle spasticity. Changes in the neuromuscular junction morphology, synaptic density reduction, and altered motor unit activation are observed post-stroke. These alterations contribute to compromised neuromuscular transmission, diminished muscle function, and structural changes in synaptic plasticity. The neuromuscular junction’s role in muscle atrophy after a stroke is an area that requires further exploration. Muscle fiber type changes involve hypertrophy of slow-twitch fibers and atrophy of fast-twitch fibers, leading to shifts in type I to type II fiber ratios. This change affects the patient’s ability to generate forces at high movement velocities. The distribution of muscle fiber types is influenced by disruptions in neurological connections, emphasizing the importance of physical exercise in post-stroke recovery to enhance neural plasticity. Central nervous system changes result in disruptions in voluntary muscle movements, varying from mild weakness to paralysis. Neurotransmitter dysfunction, particularly involving acetylcholine, contributes to impaired communication between nerves and muscles post-stroke. Depression, common after a stroke, is linked to disruptions in noradrenergic and serotonergic neurons, affecting emotions and potentially exacerbating muscle atrophy. Denervation, the damage or disconnection of motor neurons responsible for muscle innervation, occurs after a stroke, leaving muscle fibers without proper neural stimulation. This denervation leads to decreased muscle activation and, over time, muscle atrophy. Figure made in BioRender.com.

4.1 Neurotransmitter dysfunction

Neurotransmitters, such as acetylcholine, play a crucial role in transmitting signals from motor neurons to muscle fibers at the neuromuscular junction. In stroke-induced atrophy, there may be disruptions in the release or reception of neurotransmitters, leading to impaired communication between nerves and muscles, further contributing to muscle atrophy. Depression is a common occurrence post-stroke and is linked to increased disability, cognitive impairment, and mortality [56]. These symptoms are linked to noradrenergic and serotonergic neurons located in the brainstem that regulate emotions. The axons from these nerves pass through the hypothalamus, basal ganglia, corpus callosum, and the radial crown and end in the frontal cortex. Damage to these axons or the structures they pass through can lead to decreased levels of serotonin (5-HT) and norepinephrine (NE) [56, 57]. 5-HT and NE are monoamine neurotransmitters linked with depression, anxiety, self-injury, suicidal behavior, and sleep disorders [58]. Post-stroke patients are noted to have decreased levels of these neurotransmitters and are more prone to depression [57, 56].

Studies in rats have shown that reducing 5-HT reduces the excitability of neural circuits in the motor cortex [59], while selective serotonin reuptake inhibitors administered to humans enhance excitability in the motor cortex [60]. It is understood that 5-HT releases on motor circuits in the spinal cord, specifically the dorsal horn and intermediate zone of the spinal cord, thus directly affecting motor activity by depressing or facilitating transmission in afferent fibers [61]. A study done on cats exercising on a treadmill showed that incremental increases in walking speed correlated to incremental increases in the discharge frequency of single raphe-spinal fibers, which are part of the pathway that 5-HT is released from [62]. This suggests a connection between stronger muscle contractions causing increased 5-HT to amplify signals from synaptic imputes. However, too much 5-HT in the central nervous system can also limit motoneuron activation of muscles, indicating 5-HT’s complex role in depressing transmission signals [63].

4.2 Denervation

After a stroke, motor neurons responsible for innervating certain muscle fibers may become damaged or disconnected due to the brain’s impaired ability to send signals. This denervation leads to muscle fibers being left without proper neural stimulation and results in decreased muscle activation and, over time, muscle atrophy. In a study that examined hemiplegic muscles in patients, somatosensory evoked potentials, motor conduction, and synaptic conduction between the plexus and roots were assessed to determine if fibrillation was present in hemiparetic or hemiplegic muscles and whether fibrillation was affected by injuries to the peripheral nervous system [64]. It was found that fibrillation was found in both groups of patients with hemiparetic or hemiplegic muscles, especially in the distal and intermediate muscles. However, conduction abnormalities were not noted in the affected side of the body, suggesting trans-synaptic degeneration of the motor neurons rather than peripheral nerve trauma because of hemiparetic or hemiplegic contralateral cerebral lesions. Trans-synaptic degeneration, which is neuronal degradation accompanied by axonal degeneration, is known to occur in the lower motor neurons after stroke [65]. With brain ischemia, upper limb movement is more frequently affected, which has been demonstrated in an animal study involving rats [66]. In humans, denervation typically occurs in the first two to three weeks after stroke in the distal arm and hand muscles [67]. This observation is due to interruptions of the upper motoneuron pathways from the brain lesion, leading to paretic upper limbs since the motor recovery post-stroke is associated with crossing of corticospinal tract fibers from the lesion-spared motor cortex to the stroke-denervated side of the spinal cord.

4.3 Neuromuscular junction changes

The neuromuscular junction plays an integral role in regulating the contractability activity of skeletal muscles since it is responsible for transmitting action potentials from the motor neurons to the muscle fibers. Changes in neuromuscular junction morphology, including nerve terminal size and the number of active zones, have been noted in multiple diseases including congenital myasthenic syndromes [68], myasthenia gravis [69] and Lambert-Eaton myasthenic syndrome [70]. However, there is little information regarding the role that stroke plays in affecting neuromuscular junction plasticity.

It is understood that brain lesions lead to subsequent degradation of signals reaching the upper motoneuron pathways, leading to a reduction of motor units in the paretic upper limbs [66]. Additionally, motor recovery in post-stroke patients is associated with corticospinal tract fibers crossing from the lesion-spared, intact motor cortex to the stroke-denervated side of the spinal cord [71]. Thus, it is reasonable that the neuromuscular junction is altered after stroke, especially since the neuromuscular junction can adapt and maintain performance during aging through increased branching and increased area of the post-synaptic membrane [72]. A study on rats subjected to brain ischemia showed neuromuscular junction morphological changes including increased area, perimeter, fiber diameter, and relative planar area compared to the control group in muscle fibers collected from the biceps, triceps, finger flexor, and finger extensor muscles. Interestingly, this increase in morphology of the neuromuscular junction presented positive correlation in reaching and gripping performance, indicating evidence of neuromuscular compensatory mechanisms [66]. However, muscle atrophy was noted as a result of increased connective tissue proliferation in the forelimb muscles in the focal cortical ischemic rats, which was due to endothelin-1. Further studies should focus on potential biomarkers of muscle atrophy that contribute to connective tissue proliferation, fibrosis, and increased amounts of fat accumulation, all of which contribute to neuromuscular impairment and function and, eventually, muscle atrophy.

4.4 Reduced synaptic density

Skeletal muscle is the main organ effected in post-stroke patients [73]. Traditionally, post-stroke disability has been attributed to brain injury itself. However, systemic muscle mass loss and decreased muscle function after stroke cannot be fully explained by brain injury alone. Studies have shown a decrease in motor units 4 to 30 hours after cerebral infraction as a result of interruptions to prominent spinal alpha motor neurons innervating the upper muscles of the affected side [74]. Thus, a reduction in synaptic contacts between motor neurons and muscle fibers can result in diminished neuromuscular transmission, leading to compromised muscle function.

Post-stroke, early structural alterations in synaptic plasticity are characterized by swollen dendrites and the loss of dendritic spines [75]. In a mouse model of medial prefrontal cortex ischemia, dendritic branching, spine density, and mushroom-shaped spines were decreased, further confirming structural changes in synaptic activity [75]. In ischemic stroke patients, synaptic density was evaluated with magnetic resonance images and perfusion positron emission tomography 21 ± 8 days after stroke onset by targeting vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. Results showed a decrease, but residual signal within the lesion of stroke patients compared to heathy controls. Also, the protein signal was lower in the non-lesion tissue of the affected hemisphere compared to the unaffected hemisphere, further supporting a reduction in synaptic density in post-stroke patients.

4.5 Altered motor unit activation

Altered motor unit activation is a common issue after a stroke, and it is primarily related to central nervous system changes and neuromuscular adaptations that occur due to the brain damage resulting from the stroke [76]. An instance of neuromuscular adaptation was noted in the medial gastrocnemius (MG), a key postural muscle. Combined intramuscular and surface electromyograms were triggered with firing instants of motor units measured by the electromyograms. Action potentials in the paretic gastrocnemius had 33% wider skin regions compared to the non-paretic muscle. This study supports the hypothesis that stroke causes enlargements of muscle units as seen in the skin surface, indicating neuromuscular plasticity after stroke.

After cerebral stroke, a cascade of changes occurs at the supraspinal and spinal nervous system that lead to persistent motor impairment [77]. This was demonstrated by quantifying the coherence of motor unit spike trains in which different frequencies represented different levels of control. Surface electromyograms of the first dorsal interosseous muscle on both paretic and contralateral sides of stroke patients showed significantly increased delta (1–4 Hz), alpha (8–12 Hz) and beta (15–30 Hz) bands on the affected side compared to the contralateral side. However, gamma (30–60 Hz) bands remained the same. This observation demonstrated that a common synaptic input to the motor neurons of the paretic side was increased, and that these changes occur at multiple levels of the spine after a stroke.

4.6 Muscle fiber type changes

Stroke-induced muscle atrophy can also lead to changes in the distribution of muscle fiber types. Type I (slow-twitch) fibers are associated with physical activity, while type II (fast-twitch) fibers are associated with strokes [78, 79]. Stroke-affected limbs exhibit significant muscular hypertrophy of type I (slow-twitch) fibers and atrophy of type II (fast-twitch) fibers [80]. Studies have also shown that there is a shift from type II fibers to type I fibers, decreasing a stroke patient’s ability to generate forces in high movement velocities [81]. The gastrocnemius muscle is the most commonly affected by post-stroke spasticity. A study demonstrated that the shifts in the ratio of type I to type II fibers suggest a denervation-reinnervation [82]. However, other studies have shown an increase in type II fibers from type I fibers in the hemiparesis leg [83], indicating a complex muscle recomposition process across individual muscles and muscle groups that is not well understood. Furthermore, damage to specific motoneurons, such as those innervating type II fibers, may be more affected post-stroke, and thus harder to activate given that they need greater synaptic excitation due to their size [51, 84]. It is important to note that muscle atrophy is primarily understood as the result of disrupted neurological connections, leading to hemiparesis [85]. Thus, physical exercise may be one of the most effective therapies in enhancing neural plasticity in post-stroke recovery to compensate for the effects of the lesion and its negative downstream effects seen in the musculoskeletal system [86, 87, 88].

5. Other changes associated with stroke-induced atrophy

5.1 Inflammatory responses that affect the neuromuscular junction

After a stroke, inflammatory pathways are activated and can impact the neuromuscular junction and contribute to muscle weakness and atrophy. The exact mechanisms involved in this process are complex and are still an active area of research. Some specific inflammatory pathways and processes that have been implicated in affecting the neuromuscular junction after stroke include cytokine release, microglial activation, chemokines, oxidative stresses, autoimmune responses, nuclear Factor-Kappa activation, and complement activation.

One of the early events that occurs in post-ischemic brain tissue is the release of reactive oxygen species via mitochondrial and NADPH oxidase pathways, leading to oxidative damage to glial cells and neurons of the central nervous system [89]. Reactive oxygen species, as well as other molecules, released during the inflammatory response after a stroke induce the expression of NF-kB, a key transcription factor and master regulator of inflammation and immunity [34, 90, 91]. The NF-kB transcription factor is a key mediator of inflammatory cytokines, more specifically, of TNF-α and IL-1, both of which are involved in muscle atrophy after stroke [92, 93]. A strong paradigm supports the activation of NF-kB in response to stroke, which is related to blood-brain barrier disruption, inflammation [91], and neuronal death [94].

5.2 MiRNAs

MicroRNAs (miRNAs) and exosomes play significant roles in muscle atrophy following a stroke. Both miRNAs and exosomes contribute to the regulation of key pathways that impact muscle health and homeostasis. For example, miR-1, miR-133, and miR-206 are involved in the regulation of muscle protein synthesis [95]. These miRNAs can target and inhibit the expression of specific genes and signaling pathways that promote muscle protein synthesis. In stroke-induced muscle atrophy, the upregulation of certain miRNAs can contribute to reduced protein synthesis. miRNAs also participate in the regulation of muscle degradation pathways. miR-23, miR-27 [96], and miR-29 [97], for example, can target genes involved in muscle protein degradation, such as components of the ubiquitin-proteasome system and autophagy pathways. Upregulated miRNAs that target these pathways can accelerate muscle breakdown.

Meta-analysis studies have shown a link between dysregulation of miRNA and the occurrence of stroke, especially with miRNAs that are linked to the inflammatory response and toll-like receptor signaling and cytokine pathways [98]. Additionally, miRNAs can be potential biomarkers for the risk of stroke. A longitudinal study of 1914 participants, of which 138 were diagnosed with incidental stroke, showed that plasma levels of three miRNAs, miR-6124, miRNA-5196, and miR-4292, were significantly associated with increased stroke risk at the population levels. Furthermore, miR-6124 and miRNA-5196 were associated with all stroke risk factors, while miR-4292 was more related to HDL and body mass index in association to stroke risk.

5.3 MMPs

Matrix Metalloproteinases (MMPs) are a family of endopeptidases that mediate extracellular matrix (ECM) remodeling [99]. Previous studies have suggested that MMPs are upregulated in a variety of states and conditions associated with muscle atrophy, including disuse [100]. Notably, MMPs have also been implicated in ischemic stroke, with certain MMP gene polymorphisms conferring heightened vulnerability to cerebral ischemia [101, 102]. The expression of MMPs appears to be upregulated following episodes of cerebral ischemia [103, 104]. Although the relationship between stroke and MMP expression has been well studied, additional studies are needed to determine whether MMP levels following cerebral ischemia correlate with the magnitude of post-stroke muscle atrophy. Since most of the studies on the relationship between ischemia have been conducted in rodent models, further research demonstrating increased MMP expression in humans following cerebral ischemia is warranted. If MMP expression levels are positively correlated with post-stroke muscle atrophy, MMP inhibitors could be used as a therapy to minimize muscle atrophy in patients after ischemic events.

6. Conclusions

In conclusion, this paper discusses the multifaceted factors contributing to muscle atrophy following a stroke. Stroke survivors often face a complex interplay of issues, including impaired swallowing muscles, nutrient absorption problems, and inadequate protein intake, which can lead to malnutrition. The lack of essential amino acids further exacerbates muscle protein breakdown. The paper highlights the crucial role of protein synthesis in stroke-induced muscle wasting and the potential benefits of branched-chain amino acid supplementation. Physical inactivity, as a result of motor impairments and bedridden periods during the recovery phase, is another significant factor contributing to muscle disuse and subsequent atrophy. Changes in signaling pathways, particularly the IGF/Akt/PI3K pathway, play a pivotal role in muscle protein synthesis and breakdown after stroke. Dysregulation of this pathway can favor protein degradation over synthesis, leading to muscle wasting. The paper also discusses the involvement of the ubiquitin-proteasome system and autophagy in stroke-induced sarcopenia, highlighting their roles in protein degradation and muscle atrophy. Insulin resistance, often observed in stroke patients, is considered a potential link between stroke-induced muscle atrophy and diabetes, although further research is needed to establish this connection. Autonomic dysregulation, including sympathetic overactivation, is identified as a significant contributor to muscle atrophy after stroke. Additionally, hepatic dysfunction is explored as a possible connection between liver disease and stroke-induced muscle atrophy. This paper also delved into the impact of central nervous system changes, inflammatory pathways, and the role of miRNAs and exosomes in stroke-induced muscle atrophy. Matrix Metalloproteinases (MMPs) are also discussed in the context of ECM remodeling and their potential involvement in post-stroke muscle atrophy. In summary, the paper underscores the complexity of muscle atrophy in stroke survivors, involving a wide array of factors, from nutrient intake and protein synthesis to neural changes, inflammatory responses, and autonomic dysregulation. Further research and therapeutic interventions are needed to better understand and mitigate the effects of muscle atrophy in stroke patients.

7. Future directions

In light of the extensive research and insights provided on stroke-induced muscle atrophy, several promising future directions can be identified. These directions aim to address the complex interplay of factors contributing to muscle wasting in stroke survivors and provide potential avenues for intervention and treatment. Given the significant role of inadequate protein intake and malnutrition in stroke survivors, future research should focus on optimizing nutritional strategies to prevent and combat muscle wasting. Tailored dietary plans, including protein supplementation and branched-chain amino acid (BCAA) supplementation, can be explored further to improve protein synthesis and mitigate muscle atrophy. Investigating interventions that target the IGF/Akt/PI3K pathway to restore its activity holds promise. Therapies aimed at promoting this pathway’s activation could potentially ameliorate stroke-induced muscle atrophy and sarcopenia, with a focus on both rodent and human models. Further research into the UPS and autophagy mechanisms is warranted to identify potential therapeutic targets. Strategies that reduce UPS and autophagy activity may hold promise in preventing muscle protein degradation and muscle atrophy in stroke survivors.

Investigating the temporal relationship between stroke, insulin resistance, and diabetes is essential. Understanding how insulin resistance contributes to muscle atrophy and exploring interventions to improve insulin sensitivity in chronic stroke patients are crucial avenues for research. Exploring the implications of autonomic dysregulation on endocrine equilibrium and its role in driving muscle atrophy after stroke should be a focus. This includes investigating the use of adrenergic receptor blockers and other interventions to mitigate sympathetic overactivation. Research into the relationship between liver function, liver disease, and stroke-induced muscle atrophy is needed. This includes exploring the potential protective role of factors released by the liver and interventions to counteract liver-related muscle atrophy.

Further investigations into central nervous system changes, including cortical reorganization and the impact of inflammation on the neuromuscular junction, should be pursued. Understanding the complex mechanisms involved in neural and inflammatory contributions to muscle atrophy can lead to targeted interventions. Research on the regulation of miRNAs and exosomes in stroke-induced muscle atrophy should be expanded. Identifying specific miRNAs and exosomes involved in muscle protein synthesis and degradation pathways and developing interventions to modulate their activity are promising areas. The relationship between MMP expression levels and post-stroke muscle atrophy in humans should be explored further. Investigating whether MMP inhibitors can be utilized as a therapy to minimize muscle atrophy in stroke patients is a valuable direction. By pursuing these future directions, researchers can contribute to a better understanding of the multifaceted mechanisms underlying stroke-induced muscle atrophy and develop effective interventions to improve the quality of life for stroke survivors.

Acknowledgments

Preparation of this article is partially supported by the Western Michigan University Homer Stryker MD School of Medicine.

Conflicts of interest

Dr. Yong Li is one of the executive editors for Journal of Cellular Biochemistry (JCB). All other authors declare that this review was conducted in the absence of any commercial of financial relationships that could be construed as a potential conflict of interest.

Author contributions

NB, GMA, JCK, and LL contributed to the conception, writing, and design of the review. All three performed literature review and drafted separate sections of the manuscript. YL structure, read, revised, and approved the submitted manuscript.