In Parkinson’s Disease (PD), ER stress is well-established as a pivotal element in the pathogenesis within the central nervous system (Baek et al., 2019). The primary neuropathology involves the loss of dopaminergic neurons, where the accumulation of misfolded alpha-synuclein directly triggers the UPR, compromises ER function, and contributes to a toxic cycle of protein misfolding and neuronal death (Li, 2023). The vast majority of mechanistic studies on ER stress in PD have been conducted in this neuronal context.

The focus on CNS pathology often overshadows peripheral manifestations; however, PD motor symptoms like muscle rigidity and bradykinesia point to significant muscle involvement (Kong et al., 2025; Palakurthi and Burugupally, 2019). The link to ER stress in muscle is twofold. First, it can be inferred as an indirect consequence of CNS pathology; impaired neuronal signaling and motor control can lead to disuse or altered muscle activity, which are known stressors (Bernard-Marissal et al., 2015; Paschen and Doutheil, 1999). Second, and more directly, emerging evidence now suggests a primary ER stress response within muscle tissue itself, although this research is less extensive than the CNS-focused work. Studies have begun to identify UPR activation in the muscle of PD models, suggesting that the cellular stress response is not confined to the brain (Deldicque, 2013; Zhang et al., 2015; Mercado et al., 2016). This distinction is critical: muscle dysfunction may not just be a downstream effect of neurodegeneration but also a parallel pathology.

While the role of ER stress in the neurons of the AD brain is well-documented, its involvement in peripheral skeletal muscle is an area of active investigation rather than established fact. Patients with AD frequently experience significant physical decline, including muscle weakness and sarcopenia, that cannot be fully explained by cognitive impairment alone (Endres and Reinhardt, 2013; Uddin et al., 2020; Ekundayo et al., 2024). The link to ER stress in muscle is therefore largely inferred from the systemic nature of the disease. It is hypothesized that systemic factors present in AD, such as chronic inflammation or circulating amyloid-β oligomers, could induce a parallel ER stress response in muscle tissue, thereby contributing to the observed frailty (Deldicque, 2013; Burtscher et al., 2021). It is crucial to differentiate this hypothesis from the direct evidence seen in the CNS, where amyloid-β and tau aggregates are known to trigger the UPR (Li et al., 2015; Ajoolabady et al., 2022). Thus, while plausible, the contribution of muscle-specific ER stress to AD pathology requires more direct experimental validation.

An expanded CAG repeat in the huntingtin gene produces a mHTT protein with an abnormally long polyglutamine stretch, causing HD, a progressive neurodegenerative disorder (Maity et al., 2022; Gil and Rego, 2008). The accumulation of this misfolded mHTT protein within neurons induces significant ER stress and disrupts ER homeostasis (Maity et al., 2022). ER stress contributes to neuronal dysfunction, ultimately resulting in the neuronal death observed in HD.

HD is characterized by a triad of symptoms: motor impairments, cognitive decline, and psychiatric disturbances. The motor impairments—including chorea, dystonia, and rigidity—are accompanied by significant muscle atrophy and weakness that contribute substantially to functional decline (Goh et al., 2018; Mehanna and Jankovic, 2024). While direct evidence for ER stress in the muscle of HD patients is still emerging, strong indirect evidence links the pathology to this pathway. The mutant huntingtin (mHTT) protein is expressed universally, including in muscle tissue, where it forms aggregates (Jodeiri Farshbaf and Ghaedi, 2017; Barron et al., 2021). The presence of these aggregates can directly overwhelm the muscle’s protein quality control systems, such as the ER-associated degradation (ERAD) pathway, a classic trigger for the UPR. Furthermore, muscle biopsies from HD models show significant mitochondrial dysfunction and impaired autophagy, pathologies mechanistically linked to chronic ER stress. A key element of this pathology is the disruption of ER-mitochondrial crosstalk; ER stress alters calcium signaling between the two organelles, which in turn cripples mitochondrial bioenergetics and promotes cell death in muscle fibers (Maity et al., 2022; Vidal et al., 2011; Volgyi et al., 2015). Therefore, it is highly plausible that mHTT accumulation in muscle fosters a state of chronic ER stress that drives intrinsic muscle wasting (Afroze and Kumar, 2019; Hassab et al., 2023). Given this systemic pathology, investigating ER stress in peripheral tissues like muscle could uncover vital therapeutic targets beyond the brain. Strategies aimed at alleviating ER stress or improving ERAD function hold promise for improving both neurological and muscular symptoms in this devastating disease (Maity et al., 2022; Lontay et al., 2020).

ALS or Lou Gehrig’s disease, is a neurodegenerative disorder that is characterized by the selective degeneration of motor neurons in the brain and spinal cord. It is a condition that progresses rapidly and ultimately results in death (Duranti and Villa, 2023; Loeffler et al., 2016). This neuronal degeneration results in progressive muscle atrophy, weakness, and ultimately paralysis, culminating in respiratory failure (Tiryaki and Horak, 2014; Wijesekera and Leigh, 2009). ER stress affects motor neurons and skeletal muscle tissue, contributing to ALS (Zhao et al., 2022; Jeon et al., 2023).

In contrast to other neurodegenerative conditions where muscle pathology is often considered secondary or inferred from CNS dysfunction, ALS presents compelling direct evidence for ER stress as a primary event in skeletal muscle tissue (Loeffler et al., 2016).

In ALS, the buildup of misfolded proteins like mutant superoxide dismutase 1 (SOD1) and TDP-43 is a key pathological driver that directly induces ER stress in muscle. For example, mutant SOD1 is known to accumulate within the ER and on the outer mitochondrial membrane of muscle cells, where it physically disrupts protein folding machinery and impairs calcium homeostasis, leading to a robust UPR activation (Nagaraju et al., 2005; de Mena et al., 2021). Importantly, research in ALS animal models shows that markers of ER stress (e.g., CHOP, BiP) are upregulated in skeletal muscle during pre-symptomatic stages, before significant denervation occurs (Nagaraju et al., 2005; Chen et al., 2015). This early activation provides strong evidence that muscle is not a passive victim of motor neuron loss but rather a primary site of pathology, with intrinsic ER stress contributing directly to atrophy by disrupting protein translation and activating pro-apoptotic pathways (Nagaraju et al., 2005; Jesse et al., 2017; Galbiati et al., 2014). This muscle-centric pathology helps explain why the role of exercise in ALS is uniquely complex and controversial (de Almeida et al., 2012; Tsitkanou et al., 2019). While moderate activity may be beneficial, strenuous exercise is hypothesized to be detrimental by overwhelming already vulnerable motor neurons. This could occur through several mechanisms, including increased metabolic load, excitotoxicity at the neuromuscular junction, and heightened oxidative stress that the compromised neuron cannot buffer (Duranti and Villa, 2023; Siciliano et al., 2020; Dishman et al., 2006; Sheikh and Vissing, 2019; Dobrowolny et al., 2021). This potential for harm underscores that any therapeutic strategy, including exercise, must account for the primary pathology. Therefore, the strong evidence for muscle-intrinsic ER stress in ALS not only highlights a therapeutic target but also provides a rationale for extreme caution with exercise prescription, demanding highly individualized and carefully monitored programs (Table 1).

Physical exercise has a multifaceted impact on ER stress in skeletal muscle, with notable differences observed between acute and chronic exercise protocols (Petriz et al., 2017; Marafon et al., 2022). Acute exercise, including endurance and resistance activities, can trigger ER stress and activate the unfolded protein response in skeletal muscle (Bohnert et al., 2018; Egan and Sharples, 2023). This initial stress response is likely due to the increased protein synthesis demands and fluctuations in calcium levels that occur during muscle contraction (Berchtold et al., 2000; Kameyama and Etlinger, 1979). ER stress markers like BiP, CHOP, GRP94, and phosphorylated eIF2α have been found to increase in skeletal muscle after a single bout of intense exercise (Afroze and Kumar, 2019; Gallot and Bohnert, 2021; Khadir et al., 2016; Marafon, 2022). This suggests that the UPR activation following acute exercise could be an adaptive mechanism, preparing the muscle for future challenges.

Chronic regular moderate-intensity exercise induces adaptations that reduce the responses of genes and proteins associated with ER stress in skeletal muscle (Li et al., 2019; Korkmaz et al., 2023). This suggests that consistent exercise training can enhance the muscle’s ability to cope with cellular stress, potentially protecting it against subsequent stressors. However, it is crucial to note that excessive exercise intensity and volume, particularly without adequate rest and recovery, can have detrimental effects and may paradoxically increase ER stress, as observed in overtraining scenarios (Marafon et al., 2022; Pereira et al., 2016). The biphasic response of ER stress to exercise highlights the necessity of meticulously evaluating exercise prescription parameters, including intensity, duration, frequency, and rest periods, to achieve beneficial adaptations in ER health within skeletal muscle.

This distinction between the acute response and chronic adaptation can be visualized as a timeline (Figure 3). A single bout of exercise acts as a transient homeostatic challenge, causing a rapid increase in ROS and calcium flux that triggers a mild, short-lived UPR activation. This is a crucial signaling event that results in the temporary upregulation of protective chaperones and antioxidant enzymes. With consistent training over weeks and months, these repeated acute signals drive a long-term adaptive state. This chronic adaptation is characterized by an increased baseline pool of ER chaperones, greater mitochondrial efficiency, and enhanced antioxidant capacity (Hetz and Papa, 2018; Silva et al., 2022; Farrell and Turgeon, 2021). Consequently, the trained muscle exhibits lower basal ER stress and a blunted, more efficient UPR response when faced with subsequent stressors, signifying a more resilient cellular phenotype.

ER stress in skeletal muscle has been shown to be induced by both endurance (aerobic) and resistance exercise, although the specific markers and the extent of the response may vary depending on the type of exercise and the intensity of the exercise (Wang et al., 2011; Koulmann and Bigard, 2006). HIIT is emerged as a potentially beneficial exercise modality, with some studies indicating that it can lead to a decrease in ER stress markers within skeletal muscle (Kim et al., 2014; Liu et al., 2013). This finding challenges the notion that only moderate-intensity exercise is beneficial and suggests that higher intensity exercise, when appropriately managed, could trigger distinct adaptive pathways in the ER.

Regular moderate-intensity exercise appears to be generally beneficial for attenuating basal ER stress levels in skeletal muscle, promoting a more resilient cellular environment (de Sousa Fernandes et al., 2023; El Assar et al., 2022). In contrast, low-intensity exercise may be inadequate to produce notable alterations in ER stress markers, especially when conducted in a fasted condition (Marafon et al., 2022; Lee et al., 2015). Furthermore, it is important to consider that the response to exercise-induced ER stress can differ depending on the specific muscle being examined (de Sousa Fernandes et al., 2023; Kim et al., 2010; Kim et al., 2018). For instance, the soleus and EDL muscles may express different ER stress markers after the same exercise. This heterogeneity highlights the complexity of skeletal muscle and the need for tissue-specific considerations when designing exercise interventions aimed at modulating ER stress.

Several molecular mechanisms may explain how exercise modulates ER stress in skeletal muscle. PGC-1α, a key regulator of mitochondrial biogenesis and energy metabolism in muscle, is crucial for mediating exercise-induced adaptations (Afroze and Kumar, 2019; Baar, 2004; Feng et al., 2013; Lira et al., 2010). Research indicates that PGC-1α interacts with cleaved ATF6α, a transcription factor activated during the unfolded protein response (UPR), to promote an adaptive UPR in skeletal muscle post-exercise (Afroze and Kumar, 2019; Wu et al., 2011; Jung and Kim, 2014). This interaction indicates that PGC-1α is essential for ER stress adaptation in muscle, potentially improving ER health and resilience.

Exercise also increases the expression of ER chaperones, proteins that help protein folding and restore ER homeostasis, reducing ER stress (Deldicque, 2013). Interestingly, different UPR arms may play different roles in exercise adaptation. PERK/eIF2α/CHOP pathway may negatively regulate muscle homeostasis after exercise training, while the ATF6α pathway appears to be involved in adaptive response and recovery from exercise-induced damage (Afroze and Kumar, 2019; Ogborn, 2013; Chen et al., 2023; Vargas-Mendoza et al., 2019). For example, it is demonstrated that the deletion of CHOP genetic material leads to an enhancement of exercise adaptation in mice with skeletal muscle-specific PGC-1α knockout (Afroze and Kumar, 2019; Kristensen et al., 2018). Intracellular calcium level fluctuations during muscle contraction in exercise are considered a potential trigger for UPR activation (Afroze and Kumar, 2019; Ito et al., 2018; Kano et al., 2012). Additionally, Inflammation, especially with respect to the cytokine IL-6, may contribute to the intricate regulation of ER stress homeostasis during exercise (Marafon et al., 2022; Ropelle et al., 2010). The opposing roles of different UPR arms in exercise-induced muscle adaptation underscore the complexity of this cellular response and the need for targeted interventions that selectively modulate specific UPR pathways to maximize benefits (Figure 4). Table 2 summarizes what exercise does for ER stress in neurodegenerative diseases.

The progression of muscle decline in neurodegenerative diseases is not driven by a single pathway but by a destructive interplay between several cellular stress responses. The UPR, mitochondrial dysfunction, oxidative stress, and inflammation form a self-perpetuating ‘vicious cycle.’ Understanding how exercise modulates ER stress requires appreciating its ability to intervene at multiple points within this interconnected web.

In a pathological state, these four elements amplify one another. Mitochondrial dysfunction is a central node; damaged mitochondria produce less ATP and leak excessive reactive oxygen species (ROS), causing oxidative stress. This surge in ROS directly damages lipids and proteins within the ER, impairing calcium handling and protein folding, which in turn triggers the UPR (Misrani et al., 2021; Kowalczyk et al., 2021). A chronically activated UPR then feeds back to harm the mitochondria. It disrupts the critical physical and functional connection at the mitochondria-associated membranes (MAMs), impairing calcium transfer needed for bioenergetics and activating mitochondria-mediated apoptosis through effectors like CHOP. Furthermore, the UPR, particularly via the IRE1α and PERK pathways, activates pro-inflammatory signaling cascades like NF-κB and JNK (Senft and Ronai, 2015; Bravo et al., 2012). The resulting chronic inflammation closes the loop by generating more ROS and directly impairing mitochondrial function, thus perpetuating a cycle of cellular damage, energy crisis, and muscle wasting.

Exercise is uniquely positioned to break this vicious cycle and foster a ‘virtuous cycle’ of cellular health.

According to the available evidence, individuals who suffer from PD may reap significant benefits from engaging in physical activity, particularly aerobic exercise and resistance training (Falvo et al., 2008; Schootemeijer et al., 2020). Regular physical activity improves motor function, reduces bradykinesia, and enhances balance and coordination, and ultimately improve the overall quality of life for PD patients (Duranti and Villa, 2024; Borrione et al., 2014). Exercise may benefit PD muscle function by improving muscle strength, mitochondrial function, and systemic inflammation (Duranti and Villa, 2024; Kelly et al., 2014). The findings indicate a beneficial effect of exercise on motor symptoms in PD; however, the specific influence of exercise interventions on ER stress markers in the muscle tissue of Parkinson’s patients or animal models is not clearly addressed in the provided excerpts. Considering the established function of ER stress in muscle dysfunction and the capacity of exercise to influence ER stress in healthy muscle, future research should explore this relationship to enhance understanding of the mechanisms that underlie the benefits of exercise in PD and to potentially refine exercise interventions for this demographic.

Exercise training has demonstrated potential in mitigating cerebrovascular dysfunction associated with AD by influencing ER stress within the brain. Research indicates that physical activity can diminish the expression of abnormal ER stress markers in the brains of animal models of AD, specifically p-IRE1α, CHOP, and p-eIF2α (Hong et al., 2020; Lange-Asschenfeldt and Kojda, 2008; Medinas et al., 2021). This suggests that exercise can modulate ER stress-dependent endothelial dysfunction, which is linked to AD. Evidence suggests that exercise can improve cerebral blood flow, reducing amyloid-β accumulation, neuronal cell death, and cognitive decline in AD patients (Ribarič, 2022; Tan et al., 2021). While these findings highlight the neuroprotective effects of exercise in AD, research specifically examining the effects of exercise on ER stress within muscle tissue of AD models or patients and its potential contribution to improved physical function is less prominent in the provided snippets. Considering the possible association between ER stress and muscle atrophy in AD, further investigation into whether exercise also alleviates ER stress in muscle tissue in this context could provide a more complete understanding of its therapeutic benefits for both cognitive and physical function.

The research snippets provided do not specifically examine the effects of exercise interventions on ER stress and muscle function in models or patients with HD. However, one snippet (Simha et al., 2025) mentions a case study where an Ayurvedic treatment regimen, including Sida cordifolia (SC), led to improvements in motor symptoms and a decrease in ER stress in a model of HD (Simha et al., 2023; Tung et al., 2025). This suggests that interventions targeting ER stress might have the potential to improve motor function in HD. Given the contribution of ER stress in HD neuronal pathology and the evidence for mHTT expression in peripheral tissues, including muscle, more research on the effects of exercise on ER stress and muscle function is needed. Such studies may help manage this disease’s debilitating motor symptoms.

The lack of evidence for exercise interventions in HD is also due to significant practical challenges. The characteristic motor symptoms of HD, such as chorea (involuntary movements) and dystonia, make the implementation and standardization of exercise protocols extremely difficult. This creates barriers to conducting the rigorous clinical trials needed to assess both functional outcomes and underlying molecular changes like ER stress.

The impact of exercise in ALS is multifaceted and has been a topic of ongoing discussion (Chen et al., 2008). Some studies indicate that exercise may enhance the quality of life for individuals with ALS, others indicate potential negative outcomes, particularly with strenuous exercise, possibly due to increased metabolic demands on already compromised motor neurons and muscle (Duranti and Villa, 2023; de Almeida et al., 2012). Snippet (Chen et al., 2015) mentions that exercise is proved to upregulate ER stress sensors and ER chaperones in skeletal muscle, but it does not specify whether this occurs in the context of ALS. Snippets (Deldicque, 2013; Gallot and Bohnert, 2021) discuss how exercise affects muscle ER stress, which might be relevant to understanding the potential impact in ALS. However, there is a lack of direct evidence within the provided snippets regarding whether exercise interventions specifically modulate ER stress markers in the muscle tissue of ALS models or patients. The conflicting evidence surrounding exercise in ALS underscores the critical need for highly individualized and carefully monitored exercise programs for individuals with this condition. Future research should aim to elucidate how different exercise regimens affect ER stress in muscle in ALS, which could help in developing safer and more effective exercise guidelines for this vulnerable population (Tables 1, 2, Figure 5).

While this review highlights the therapeutic potential of exercise, it is crucial to acknowledge that its effects are not universally positive and the literature contains significant contradictory evidence, particularly for ALS. The concept of hormesis is central: while moderate stress can be adaptive, excessive stress can be damaging, and this balance is especially delicate in neurodegenerative diseases.

The controversy is most pronounced in ALS, where some studies have even suggested a link between elite athletic activity and an increased risk of developing the disease (Hu and Robertson, 2020; Chapman et al., 2023). Furthermore, preclinical studies in SOD1 mutant mouse models have shown conflicting results based on exercise intensity. While moderate, voluntary wheel running has sometimes shown modest benefits or no effect, forced, high-intensity exercise (such as forced treadmill running or swimming) has been demonstrated to accelerate disease onset, worsen motor neuron loss, and shorten lifespan (Hu and Robertson, 2020; Scaricamazza et al., 2024; Manzanares et al., 2018). These negative outcomes are thought to result from exacerbating the underlying pathology, including overwhelming cellular bioenergetics and increasing oxidative stress on already vulnerable motor neurons.

This “double-edged sword” concept, while most stark in ALS, is relevant across all neurodegenerative diseases. In advanced stages of PD or AD, for instance, high-intensity exercise could increase the risk of falls, injury, or adverse cardiovascular events (Berg and Cassells, 1992; Ernst et al., 2023). Therefore, the key takeaway is that the intensity, duration, and type of exercise are critical variables that determine whether the outcome is beneficial or detrimental. Future research must move beyond simply asking if exercise is helpful and focus on defining precise, safe, and effective exercise prescriptions tailored to the specific disease, its stage, and the individual patient’s capacity.

To properly contextualize these findings, it’s important to frame the therapeutic potential of exercise within the current pharmacological landscape. While the ER stress markers discussed are clear pathological contributors, there are currently no FDA-approved drugs that directly target these core Unfolded Protein Response (UPR) pathways for treating neurodegenerative diseases. Research into pharmacological interventions is ongoing, with promising strategies like chemical chaperones (e.g., TUDCA and sodium phenylbutyrate) remaining largely investigational (Ioannou et al., 2025). This therapeutic gap underscores the immense value of non-pharmacological approaches like exercise, which offers a readily available strategy to enhance cellular resilience.

Furthermore, it is critical to address the limitations of extrapolating findings from preclinical rodent models to human conditions. Animal models often fail to capture the complexity of sporadic human diseases, which arise from a mix of genetic and environmental factors. The accelerated disease progression in a short-lived animal does not fully mimic the decades-long development in humans (Alexandra Lopes and Guil-Guerrero, 2025). Significant physiological and metabolic differences mean that the dose, type, and cellular response to an exercise intervention in a mouse cannot be directly translated to a human patient. Therefore, while animal models provide a strong rationale for exercise, their findings must be interpreted with caution.

Finally, future research must carefully consider several potential confounders that influence the relationship between exercise and ER stress. A patient’s diet, for instance, can independently modulate ER stress (Singh et al., 2024; Stults-Kolehmainen and Sinha, 2014). The presence of comorbidities like obesity or type 2 diabetes can create a high basal stress level that may blunt the benefits of exercise (Colberg et al., 2010; Zahalka et al., 2019). Moreover, sex differences and an individual’s lifelong training history are critical factors that can alter the cellular response to an exercise bout. Future clinical trials must be designed to control for these variables to develop truly personalized exercise prescriptions.