Impact of exercise on immune cell infiltration in muscle tissue: implications for muscle repair and chronic disease

Abstract

Exercise has long been recognized for its systemic health benefits, including modulation of the immune system. Contemporary scientific inquiry has increasingly turned toward understanding the regulatory effects of exercise on immune cell dynamics within muscle tissue, highlighting their potential role in facilitating tissue repair and modulating chronic disease pathways. Following acute bouts of exercise, especially those involving eccentric or high-intensity contractions, muscle fibers experience micro-damage that triggers a well-orchestrated immune response. This phenomenon entails a coordinated, time-sensitive accumulation of immune effector cells—namely neutrophils, macrophages, and T lymphocytes—within compromised muscle tissue. Through the release of immunoregulatory and regenerative mediators like cytokines and growth factors, these cells actively participate in coordinating tissue repair by eliminating cellular debris and resolving inflammation.

Macrophage polarization from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype is particularly crucial in coordinating effective muscle repair and preventing fibrosis. However, dysregulation of this immune response, such as persistent inflammation or impaired immune cell transition, can hinder regeneration and contribute to the pathogenesis of chronic conditions like sarcopenia, insulin resistance, and muscular dystrophies. Moreover, in chronic disease states, immune cell infiltration into muscle may become maladaptive, exacerbating tissue damage and metabolic dysfunction.

Regular moderate-intensity exercise appears to modulate this immune infiltration in a way that enhances repair mechanisms while reducing chronic inflammation, highlighting a potential therapeutic avenue for managing muscle-related pathologies. In-depth insight into the molecular and cellular crosstalk between physical activity and immune cell regulation in muscle tissue forms the basis for crafting specialized therapeutic strategies aimed at facilitating muscle regeneration and limiting the development of chronic pathological conditions. Through a detailed evaluation of exercise-elicited immune dynamics, this review underscores the dichotomous functions of immune cell infiltration in supporting muscle regeneration and in contributing to strategies for chronic disease prevention and management.

Introduction

Functioning as a metabolically responsive and structurally modifiable tissue, skeletal muscle is indispensable for motor function, metabolic stability, and the preservation of organismal homeostasis [1, 2]. Skeletal muscle regeneration represents a complex and temporally orchestrated biological event, driven by the synergistic activity of local muscle cells and a carefully modulated, short-term influx of immune cells [3, 4]. Immune cell dynamics within muscle tissue have garnered significant interest due to their dual roles in promoting tissue regeneration and contributing to chronic inflammation, depending on context and cellular phenotypes [3, 5, 6]. Physical exercise—both acute and chronic—has been recognized as a powerful modulator of immune function, capable of reshaping immune cell behavior, phenotype, and tissue-specific infiltration patterns [7, 8]. A comprehensive understanding of how immune responses activated by physical activity affect muscle tissue is pivotal for delineating the molecular and cellular mechanisms that govern both muscle repair and the progression or mitigation of chronic diseases including sarcopenia, muscular dystrophy, and metabolic syndrome.

In instances of acute muscular damage arising from traumatic impact or atypical intense exercise, the immune system serves as a central coordinator, initiating and regulating the complex biological events required for effective tissue repair. During the initial stages of muscle repair, the infiltration of neutrophils and pro-inflammatory (M1-like) macrophages plays a crucial role in debris clearance and in orchestrating the subsequent regenerative phase [7, 9–12]. In the later phase, anti-inflammatory (M2-like) macrophages along with regulatory T cells (Tregs) assume a dominant role, contributing to the repair of damaged tissue and the activation of satellite cells [9, 12]. The temporal and phenotypic plasticity of these immune cells is crucial; dysregulation can lead to impaired regeneration or fibrosis [4, 13]. Evidence from human and animal research demonstrates that exercise-induced muscle trauma, notably from eccentric contractions, provokes a biphasic immune infiltration response akin to that seen in acute injury, underscoring the ability of physiological stimuli to effectively activate and regulate the tissue repair cascade [14–16].

Exercise is increasingly recognized for its systemic immunomodulatory effects. Ongoing participation in physical exercise is associated with lowered levels of chronic inflammation, improved immunological surveillance, and enhanced immune competence, effects that are especially pronounced in aging individuals [17–19]. These effects are partially mediated through muscle-derived cytokines and myokines—such as IL-6, IL-7, and IL-15—which influence leukocyte trafficking, differentiation, and function [20–22]. Transient elevations of IL-6 induced by exercise confer dual pro- and anti-inflammatory actions, promoting neutrophil mobilization and the subsequent induction of anti-inflammatory factors such as IL-10 and cortisol [23]. Hence, skeletal muscle acts as an endocrine entity that modulates immune system interactions, with this crosstalk being especially prominent in the context of exercise and its aftermath.

Exercise characterized by differing modalities and intensities elicits variable effects on immune cell dynamics and the resultant muscular adaptation. Resistance training, for instance, is known to increase satellite cell activation and local macrophage accumulation, which are vital for hypertrophy and repair [24, 25]. Endurance exercise, on the other hand, seems to elicit more systemic immunological changes, such as improved leukocyte trafficking and redistribution [8]. Interestingly, chronic endurance training has been linked to reduced muscle-resident pro-inflammatory macrophages and increased Treg populations, suggesting a protective, anti-inflammatory muscle milieu [26–29]. Exercise-induced adaptations may serve as the underlying mechanisms driving improved insulin sensitivity and reduced muscle complications in the context of metabolic disorders [30, 31].

In aging populations and those with chronic diseases, immune cell behavior within muscle tissue can be pathologically altered. Characterized by chronic low-grade inflammation ("inflammaging") and diminished immune cell function, sarcopenia denotes the age-associated decline in muscle mass and performance [32–34]. In this setting, macrophages may become skewed toward a pro-inflammatory phenotype, and T cell infiltration may become dysregulated, contributing to anabolic resistance and poor regenerative capacity [33–35]. Exercise has been shown to partially reverse these changes, with evidence of restored macrophage polarization, increased muscle Treg abundance, and enhanced regenerative signaling pathways [4, 5, 35, 36]. Collectively, these observations suggest that the immune system constitutes a potential therapeutic target for the treatment of sarcopenia and other muscle-wasting pathologies.

Similarly, skeletal muscle in chronic metabolic diseases, including obesity and type 2 diabetes, undergoes immune cell infiltration and persistent low-grade inflammation, thereby exacerbating insulin resistance and compromising metabolic function [4, 37–39]. Exercise interventions have demonstrated the ability to reduce intramuscular macrophage content and shift their phenotype toward an anti-inflammatory profile [40–42]. Additionally, exercise-induced increases in mitochondrial biogenesis and autophagy within muscle cells may be indirectly regulated through immune-mediated pathways [43, 44]. Thus, the interaction between exercise, immune cell infiltration, and muscle health has profound implications for both disease prevention and treatment.

While existing studies have provided insights into individual components of the exercise–immune–muscle axis, a comprehensive understanding that bridges molecular mechanisms, physiological outcomes, and clinical implications is still lacking. Current literature is fragmented across disciplines such as immunology, exercise physiology, and regenerative medicine, often with inconsistent terminologies and methodologies. Moreover, the translational potential of these findings—especially in the context of chronic disease and aging—has not been fully explored.

This article aims to comprehensively review current evidence on the influence of exercise on immune cell infiltration into skeletal muscle, highlighting how these interactions affect tissue repair and the course or reversal of chronic disease. By integrating findings from basic science, clinical research, and translational studies, we seek to highlight key mechanisms, identify gaps in the literature, and propose future directions for research in this emerging interdisciplinary field.

Exercise-induced muscle damage and the initial immune response

Muscle damage induced by exercise (EIMD) constitutes a biological response to physical activity, predominantly when the activity is new, vigorous, or involves a significant eccentric contraction component [14]. Eccentric muscle contractions, involving the lengthening of muscle under tension, induce substantial mechanical stress that produces microdamage within the myofibrils, the fundamental structural units of muscle tissue [45]. This stress also disrupts the integrity of the sarcomeres, especially the Z-disks, which anchor the contractile filaments [14]. In addition to mechanical forces, metabolic stress resulting from intense muscle activity and subsequent disruptions in the delicate balance of calcium ions within the muscle cells also contribute to the overall extent of muscle damage [14, 46]. The integrity of the sarcolemma, which envelops each muscle fiber, is disrupted by injury, resulting in the efflux of diverse intracellular substances into the extracellular compartment. The released intracellular contents consist of a broad spectrum of molecules identified as damage-associated molecular patterns (DAMPs). Among the DAMPs are nuclear and mitochondrial DNA fragments, adenosine triphosphate (ATP), and proteins such as high mobility group box 1 (HMGB-1) [4, 14, 47]. These molecules serve as pivotal danger signals, effectively communicating tissue injury to the immune system and prompting the initiation of inflammation.

The first phase of the immune response following EIMD is marked by a prompt accumulation of neutrophils, the most abundant granulocytes in the bloodstream, within the damaged muscle tissue. This infiltration can occur remarkably quickly, often within just one hour following the onset of muscle injury [14, 48, 49]. Neutrophil trafficking to areas of tissue damage is mediated by diverse chemoattractant molecules. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are examples of pro-inflammatory cytokines emitted by the damaged and stressed skeletal muscle fibers themselves [49]. Subsequently, the primary cytokines stimulate endothelial cells lining the local vasculature to secrete further essential signaling molecules, most notably IL-6 and IL-8 (also referred to as CXCL8) [50, 51]. A key neutrophil chemoattractant, IL-8, directs the trafficking of these cells from the circulation into the interstitial compartment encasing the damaged muscle fibers [49] (Fig. 1).

Fig. 1.

A graphical depiction of exercise-related muscle injury, showing damaged muscle fibers, the release of damage-associated molecular patterns, and neutrophil recruitment orchestrated by inflammatory signaling mechanisms

Upon infiltration of injured muscle, neutrophils perform vital tasks that support the initial stages of the repair process. Neutrophils principally contribute to tissue cleanup by engulfing and degrading necrotic material and cellular debris through phagocytosis [52–54]. This clearance of damaged components is essential for preparing the tissue for subsequent regeneration. The inflammatory environment is augmented by activated neutrophils through the discharge of various mediators, such as pro-inflammatory cytokines (TNF-α, IL-1, IL-8), proteolytic enzymes, and reactive oxygen species (ROS) [54–56]. By promoting tissue breakdown, this inflammatory mechanism also plays a key role in directing immune cells—especially monocytes that differentiate into macrophages—to the site of injury [57, 58]. Though neutrophils play an indispensable role in starting tissue repair, their functions need to be tightly controlled. Excessive or persistent neutrophil activity may contribute to secondary damage in muscle by releasing harmful cytotoxic molecules that damage nearby healthy tissue [59].

The primary event subsequent to EIMD is the liberation of DAMPs, acting as alert signals to initiate immune activation [60]. These molecular cues induce the release of pro-inflammatory cytokines from damaged muscle, which then direct neutrophils to infiltrate the injured tissue [51, 61]. Neutrophils contribute to the elimination of cellular debris by phagocytosis and simultaneously amplify inflammation by releasing diverse cytokines and reactive oxygen species. The first inflammatory phase, largely controlled by neutrophils, constitutes a critical preparatory step for muscle tissue repair and regeneration. However, the intensity and duration of this early immune response must be carefully balanced to ensure efficient debris removal without causing excessive secondary damage to the surrounding healthy muscle tissue [62] (Fig. 2).

Fig. 2.

S A visual depiction highlighting the early immune system activation in response to exercise-induced muscle injury (EIMD). Following muscle injury, DAMPs such as ATP and HMGB-1 are released from damaged fibers, promoting neutrophil infiltration at the site of damage. Neutrophils facilitate debris clearance via phagocytosis and contribute to inflammation amplification through secretion of pro-inflammatory cytokines, proteolytic enzymes, and reactive oxygen species (ROS). The process plays an indispensable role in initiating tissue regeneration but demands rigorous control to minimize additional injury to healthy muscle tissue

It is important to note that the magnitude and kinetics of the immune response to EIMD can vary substantially depending on several factors, including the type of exercise performed (e.g., resistance vs. endurance), the training status and age of the individual, and the species or model system used in experimental studies [63, 64]. For instance, trained individuals often exhibit a blunted inflammatory response compared to untrained counterparts, and older adults tend to display delayed immune resolution, contributing to impaired regeneration. Likewise, interspecies differences in immune cell kinetics and cytokine profiles can influence the generalizability of findings from animal models to human physiology [65].

The role of macrophages in muscle repair and regeneration

Monocytes are recruited from circulation to damaged muscle tissue after neutrophil infiltration and undergo differentiation into macrophages at the site [66–69]. Macrophages possess high plasticity, which permits them to develop specialized functional phenotypes in response to specific stimuli within their microenvironment. Following exercise-induced muscle injury, macrophages primarily present a pro-inflammatory M1 phenotype and begin to infiltrate the tissue within a 4–24-h timeframe [70]. Subsequently, these M1 macrophages, or newly recruited monocytes, undergo a critical phenotypic switch, transitioning toward an anti-inflammatory and pro-regenerative phenotype known as M2 macrophages [71]. This shift in macrophage polarization generally becomes evident around 24–48 h post-injury, with M2 macrophages becoming the dominant population thereafter [58]. This critical change is influenced by macrophages clearing apoptotic neutrophils, a local cytokine shift characterized by lowered pro-inflammatory and elevated anti-inflammatory cytokines like IL-10 and TGF-β, and the effective engulfment of damaged muscle tissue debris [72].

M2 macrophages serve a vital, multifaceted role in both mitigating inflammation and encouraging muscle regeneration subsequent to exercise-induced muscle injury [58, 71]. By secreting a range of anti-inflammatory cytokines including IL-4, IL-10, TGF-β1, and IGF-1, these cells critically contribute to dampening early pro-inflammatory signals, diminishing reactive oxygen species, inhibiting neutrophil recruitment, and facilitating neutrophil apoptosis and subsequent clearance [73–75]. M2 macrophages critically contribute to muscle regeneration by driving the proliferation and differentiation of myoblasts, the muscle progenitor cells that fuse to develop new muscle fibers, resulting in restored muscle function [76, 77]. They further participate in extracellular matrix (ECM) remodeling, the scaffold supporting muscle fibers, alongside driving angiogenesis, the creation of new blood vessels [78, 79]. The reestablishment of tissue integrity and a functional vascular network, essential for nutrient and oxygen provision to muscle during regeneration, relies on ECM remodeling and angiogenesis. Lactate, produced as a metabolic by-product by skeletal muscle and macrophages during exercise, has been found to drive macrophage polarization toward an anti-inflammatory (M2) state, facilitating muscle vascular remodeling and regeneration [80, 81].

While the coordinated actions of macrophages are crucial for effective muscle repair, disruptions in their activity and phenotypic switching can lead to detrimental outcomes. For instance, persistent inflammation, often associated with a prolonged presence of M1 macrophages or a failure in the timely transition to the M2 phenotype, can impede the regenerative processes and result in the excessive accumulation of fibrous connective tissue, a condition known as muscle fibrosis [82]. Conversely, an insufficient infiltration of macrophages to the injured muscle or an impairment in their ability to effectively phagocytose necrotic fibers and cellular debris can delay the necessary clearance of damaged tissue, thereby hindering the initiation of the subsequent regenerative phases [11, 83]. Notably, certain widely used recovery methods, including cooling therapy and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) immediately after muscle injury, may hinder muscle regeneration by altering macrophage infiltration and impeding the essential transition to the anti-inflammatory M2 phenotype [83, 84].

As mentioned before, the process of muscle repair following exercise-induced damage is critically dependent on the sequential actions and phenotypic switching of macrophages. During the initial response, M1 macrophages exhibiting pro-inflammatory properties enter the injured tissue, contributing to both the inflammatory process and debris clearance. A transition to the anti-inflammatory M2 macrophage phenotype follows, which is critical for dampening inflammation, facilitating muscle precursor cell differentiation, and enabling extracellular matrix remodeling. Any imbalance or dysregulation in this carefully orchestrated macrophage response, whether it manifests as prolonged inflammation or impaired function, can significantly compromise the efficiency of muscle repair and potentially contribute to the development of chronic muscle pathologies [71, 85, 86]. Therefore, gaining detailed knowledge of how macrophage polarization and function are modulated during muscle repair is critical for the advancement of targeted therapeutic interventions to facilitate muscle injury recovery and treat muscle disorders involving disrupted regeneration or ongoing inflammation (Fig. 3 and Table 1).

Fig. 3.

Illustration of macrophage polarization during muscle repair. Monocytes differentiate into pro-inflammatory M1 macrophages that clear debris and secrete cytokines. Over the course of repair, macrophages polarize to the anti-inflammatory M2 phenotype, releasing IL-10, TGF-β, and other mediators that help resolve inflammation, drive myoblast proliferation, facilitate extracellular matrix remodeling, and advance muscle regeneration. This tightly regulated switch is essential for effective healing following exercise-induced muscle damage

Table 1.

Key functions and markers of macrophage phenotypes in muscle repair

Feature	M1 macrophages (Pro-inflammatory)	M2 Macrophages (anti-inflammatory/pro-regenerative)
Timing	Early infiltration (4–24 h post-injury)	Later infiltration (24–48 h post-injury and beyond)
Key functions	Phagocytosis of debris, secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), initiation of myoblast proliferation	Resolution of inflammation, secretion of anti-inflammatory cytokines (IL-4, IL-10, TGF-β, IGF-1), promotion of myoblast differentiation and fusion, ECM remodeling, angiogenesis
Key cytokines	TNF-α, IL-1β, IL-6	IL-4, IL-10, TGF-β, IGF-1
Metabolism	Primarily glycolysis [87]	Primarily fatty acid oxidation [88]
Stimuli	DAMPs, IFN-γ, LPS [89]	Apoptotic cells, IL-4, IL-13 [89], IL-10, TGF-β
Markers (Examples)	CD86 [4], iNOS [87]	CD206 [90], Arginase-1

In addition to cytokine-mediated signaling, macrophage polarization is tightly coupled to underlying metabolic programming. M1 macrophages predominantly rely on aerobic glycolysis and demonstrate disrupted tricarboxylic acid (TCA) cycle flux, whereas M2 macrophages engage in oxidative phosphorylation (OXPHOS) and fatty acid oxidation to sustain their anti-inflammatory and reparative functions [91, 92]. These metabolic states actively regulate macrophage function and fate rather than serving merely as by-products of activation. Exercise influences systemic and local nutrient availability, redox status, and energy substrate distribution, all of which contribute to macrophage phenotype regulation via immune-metabolic crosstalk [93, 94]. This concept underscores the emerging view that nutrient sensing mechanisms represent a critical regulatory axis in mediating immune adaptation to exercise-induced muscle injury.

Lymphocytes and T-cells in muscle adaptation to exercise

The early conceptualization of immune responses following exercise-induced muscle damage emphasized myeloid cells such as neutrophils and macrophages, yet more recent findings have highlighted the significant involvement of lymphocytes, especially T cells, in the elaborate processes governing muscle repair and regeneration [6, 95]. Contrary to their traditional association with pathological muscle degeneration in disease states, recent studies have demonstrated that lymphocytes actively infiltrate damaged muscle tissue following exercise, suggesting their participation in the subsequent repair mechanisms [96, 97]. Both animal models and human studies have provided evidence of a notable accumulation of T cells within damaged muscle fibers after exercise, indicating a more direct role in muscle adaptation than previously appreciated [96, 97].

Within the lymphocyte population, different T cell subsets exhibit specialized functions that contribute to the overall muscle adaptation response to exercise. Eccentric exercise has been associated with an increased infiltration of CD8 + T cells into the muscle tissue [98]. This increase is particularly pronounced after repeated bouts of such exercise, suggesting a potential role in muscle adaptation and repair, possibly contributing to the reduced damage seen with subsequent exercise sessions. CD4 + T cells also play important roles, with regulatory T cells (Tregs) being of particular interest in the context of muscle repair. Tregs are known for their ability to suppress excessive inflammation, a critical function in ensuring that the inflammatory response to EIMD does not become detrimental. Additionally, regulatory T cells contribute to the macrophage phenotypic conversion from a pro-inflammatory M1 to an anti-inflammatory, pro-regenerative M2 state [95, 99–102]. Of particular interest, Tregs secrete amphiregulin, a growth factor proven to stimulate muscle stem cell activity, thereby playing a central role in muscle regeneration [95].

The repeated bout effect, referring to the attenuation of muscle soreness and damage with repeated execution of the same exercise, has been widely explored within the scientific community [103]. Increasing data support the involvement of the immune system, with a particular emphasis on T cells, in driving this adaptive response [104, 105]. The recurrent recruitment of T cells to muscle tissue after repeated injury suggests the possibility of an adaptive immune imprint that facilitates faster recovery, although this remains an emerging concept and requires further validation, particularly in human studies. The initial damage to muscle tissue is thought to produce unique peptides that are later presented via major histocompatibility complex (MHC) molecules, enabling their identification by T cells [98]. Through early sensitization, the immune system may become primed to initiate a quicker and more robust reaction when the same type of muscle damage recurs (Fig. 4).

Fig. 4.

A schematic portrayal of how lymphocytes, notably T cells, participate in the recovery and regeneration of muscle tissue after damage induced by exercise. CD8 + T cell infiltration into compromised muscle regions may be involved in initiating or enhancing adaptive tissue responses. By producing IL-10, Tregs contribute to immune regulation by suppressing inflammatory activity and supporting the conversion of macrophages from the M1 phenotype to the M2 anti-inflammatory profile. Tregs also release amphiregulin, a growth factor that activates muscle stem cells, supporting tissue regeneration and contributing to the repeated bout effect

In summary, lymphocytes, particularly various subsets of T cells, are increasingly recognized as active participants in the muscle repair process following exercise. Different T cell populations, including CD4 +, CD8 +, and Tregs, contribute to this process through distinct mechanisms, ranging from direct involvement in muscle adaptation to the regulation of inflammation and the activation of muscle stem cells. T cell-driven immune responses are thought to contribute to the repeated bout effect, reflecting a muscle-associated immunological memory that enables accelerated recovery and improved adaptation to successive exercise-induced stress. Investigating the functional dynamics and mechanistic contributions of lymphocyte subsets to muscle adaptation may offer valuable insights for tailoring exercise programs and accelerating recovery from damage caused by physical exertion.

Signaling pathways governing immune cell infiltration and activity

A complex signaling framework controls the immune cell engagement and infiltration in muscle tissue in response to exercise, underscoring the tightly regulated nature of this physiological interaction [106]. Muscle contraction during physical activity leads to the liberation of myokines, signaling entities capable of exerting effects on immune cells both within the muscle microenvironment and at distant sites [107, 108]. Early after exercise, pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 are released, shaping the initial inflammatory landscape and aiding the recruitment of immune cells to areas of muscle injury. The secretion of anti-inflammatory cytokines, notably IL-10 and TGF-β, during the later repair phase is critical for dampening inflammation and advancing regenerative mechanisms in muscle tissue [89]. The myokine IL-6 demonstrates context-dependent duality in its inflammatory role, manifesting pro- or anti-inflammatory effects based on exercise duration, intensity, and specific physiological circumstances.

Exercise-induced muscle tissue infiltration by distinct immune cell populations is largely controlled by chemokines, notably IL-8 (CXCL8) and MCP-1 (CCL2), which govern their precise recruitment [109]. These chemoattractants provide directional cues, guiding neutrophils, monocytes, and T cells to the precise location of muscle injury [49]. This ensures that the appropriate immune cells arrive at the right time and place to carry out their specific functions in the repair process.

In addition to cytokines and chemokines, adenosine triphosphate (ATP), released from damaged muscle cells into the extracellular space, acts as an important signaling molecule for immune cells. Extracellular ATP functions to recruit monocytes to sites of tissue damage while concurrently engaging purinergic receptors found on the membranes of different immune cells. This activation can influence their subsequent behavior, including the release of cytokines and other signaling molecules [102, 110, 111]. It is thought that the release of ATP from damaged muscle may serve as a direct communication mechanism between muscle cells and monocytes, particularly in the context of exercise-induced muscle damage [89].

Beyond these key signaling molecules, a variety of intracellular signaling pathways within muscle cells are activated by the mechanical and metabolic stresses of exercise. Signaling cascades including calcineurin, calcium/calmodulin-dependent protein kinase (CaMK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), nuclear factor kappa B (NF-κB), and AMP-activated protein kinase (AMPK) control the synthesis and release of cytokines and other signaling factors that interact with immune cells [112–115]. Furthermore, specific metabolic pathways within immune cells themselves are also modulated by exercise. The involvement of the mTORC1-HIF1α-glycolysis pathway in enhancing macrophage polarization to the pro-inflammatory M1 state through branched-chain amino acids (BCAAs) has been established in the context of muscle repair [71]. Additionally, exercise can modulate the P2X4 receptor pathway in macrophages, which has implications for the perception of inflammatory muscle pain [116] (Fig. 5).

Fig. 5.

A visual representation of the cascade of signaling processes initiated in skeletal muscle in response to exercise stimuli. The secretion of cytokines (e.g., TNF-α, IL-1β, IL-6), chemokines (e.g., IL-8, MCP-1), and ATP by damaged muscle fibers facilitates the directed recruitment and functional activation of immune cells including neutrophils, monocytes, and T cells. Intracellular signaling pathways (e.g., CaMK, MAPK, PKC, NF-κB, AMPK) regulate cytokine production, coordinating inflammation and repair in response to mechanical and metabolic stress

The response of immune cells to exercise in muscle tissue is orchestrated by a complex interplay of signaling events. A range of signaling molecules is released in response to exercise, including cytokines with diverse inflammatory functions, chemokines that orchestrate the migration of immune cells, and ATP that acts as an early-warning signal. These extracellular signals interact with immune cells, influencing their recruitment, activation, and polarization within the muscle tissue. Simultaneously, intracellular signaling pathways within muscle cells are activated by the stresses of exercise, contributing to the broader communication network with the immune system through the release of various mediators. One pivotal mediator linking mitochondrial metabolism, immune function, and exercise adaptation is peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [117–119]. PGC-1α is a master regulator of mitochondrial biogenesis and oxidative phosphorylation in skeletal muscle and is strongly induced by endurance and resistance exercise [118, 119]. In addition to enhancing mitochondrial content and oxidative metabolism, PGC-1α plays a direct role in suppressing inflammation through modulation of NF-κB signaling and promotion of anti-inflammatory cytokines such as IL-10 [117–119]. Recent studies indicate that PGC-1α activity can influence macrophage polarization, encouraging the transition toward an M2 phenotype and promoting tissue repair and metabolic homeostasis [117–119]. As such, PGC-1α sits at the intersection of metabolic regulation and immune function, highlighting a key pathway through which exercise enhances both regeneration and immunological resilience.

An in-depth knowledge of these sophisticated signaling pathways underpins the formulation of targeted treatments that modulate immunity and promote efficient muscle repair in a range of physiological and disease-related contexts (Table 2).

Table 2.

Examples of myokines and their immunomodulatory effects

Myokine	Primary stimulus for release	Main immunomodulatory effects	References
IL-6	Muscle contraction	Both pro- and anti-inflammatory effects depending on context; promotes glucose uptake; mobilizes energy substrates	[120–122]
IL-10	Muscle contraction	Anti-inflammatory; suppresses pro-inflammatory cytokines; promotes M2 macrophage polarization	[89]
IL-15	Muscle contraction	Supports T cell homeostasis and memory cell expansion; promotes NK cell proliferation	[22, 123–125]
Brain-derived neurotrophic factor (BDNF)	Exercise	May have immunomodulatory effects; role in muscle repair and regeneration 61	[126]
Fibroblast growth factor 21 (FGF21)	Exercise	Emerging evidence suggests potential immunomodulatory roles	[126]
Irisin	Exercise	May have anti-inflammatory effects; involved in energy metabolism 61	[126]

Impact of exercise on immune cell infiltration in chronic muscle diseases

The effects of exercise on immune cell infiltration in muscle extend past immediate injury responses, exerting a vital influence on the pathophysiology of long-term muscle diseases. Sarcopenia, the deterioration of muscle mass and functionality with age, is associated with sustained low-grade inflammation—"inflammaging"—and altered immune cell dynamics in muscle [33, 34]. Significantly, physical exercise—particularly resistance training—has been shown to influence immune cell infiltration within aged muscle, with data suggesting a potential transition of macrophages toward the anti-inflammatory (M2) phenotype [127]. Physical activity is associated with a reduction in both the basal inflammatory status and the persistent inflammation characteristic of aging muscle tissue [128]. These observations support the notion that exercise can attenuate sarcopenia-associated chronic inflammation by altering immune cell activity within muscle tissue. Additionally, age-related immune dysfunction—or immunosenescence—including the accumulation of senescent T cells, has been implicated in the chronic low-grade inflammation seen in sarcopenia {Barbé-Tuana, 2020 #1540;Ray, 2018 #1539}. These dysfunctional T cells may further impair tissue regeneration and amplify inflammatory signaling {Sun, 2023 #1542;Moon, 2023 #1541}.

Muscular dystrophies, such as the progressive muscle-wasting disorder Duchenne muscular dystrophy (DMD), are characterized by ongoing muscle damage and a persistent state of inflammation, accompanied by significant infiltration of various immune cell types into the muscle tissue [129, 130]. While the infiltration of immune cells is known to contribute to the muscle-wasting process in these conditions, the role of exercise in managing the chronic inflammatory environment is complex and requires careful consideration. Regulatory T cells (Tregs) have been identified as potentially beneficial in DMD by their ability to attenuate the excessive inflammation [99]. Notably, exercise has been shown—primarily in animal models—to increase the number of Treg cells within muscle tissue. While this suggests potential for carefully designed exercise programs to offer long-term benefits, evidence in humans, particularly in chronic disease contexts such as DMD, remains limited and requires further validation [131, 132].

Inflammatory myopathies, a group of autoimmune disorders that includes conditions like polymyositis, dermatomyositis, and inclusion body myositis, are characterized by inflammation within the muscles, leading to muscle weakness [133]. These conditions are marked by the infiltration of various immune cells, including T cells and macrophages, into the affected muscle tissue [134, 135]. Research has indicated that exercise can be a safe and potentially beneficial adjunct therapy for patients with inflammatory myopathies, particularly during stable phases of the disease [136]. Supervised exercise programs have been shown to improve muscle performance and potentially reduce the levels of inflammation in these individuals [137]. Furthermore, exercise may play a role in preventing muscle atrophy that can result from the chronic inflammation and reduced physical activity often associated with these conditions [136, 137]. This suggests that exercise can be a valuable tool in managing inflammatory myopathies by improving muscle health despite the underlying autoimmune inflammation.

In summary, physical exercise has a demonstrable impact on immune cell infiltration in the context of chronic muscle diseases, often exhibiting an anti-inflammatory effect. However, the specific influence of exercise can vary depending on the particular disease, as well as the type, intensity, and duration of the exercise performed. Evidence suggests that exercise may offer therapeutic benefits in managing conditions such as sarcopenia and inflammatory myopathies by modulating the activity of immune cells within the muscle. Therefore, it is crucial that exercise interventions for chronic muscle diseases are carefully tailored to the specific characteristics of each condition to maximize potential benefits while minimizing any potential risks.

Exercise immunology and systemic chronic diseases

The influence of exercise on immune cell activity extends beyond the realm of muscle-specific conditions, playing a significant role in the prevention and management of various systemic chronic diseases. Metabolic disorders, such as type 2 diabetes and obesity, are often characterized by impaired insulin sensitivity and glucose regulation. Exercise has been consistently shown to improve these metabolic parameters [138]. Furthermore, exercise can effectively reduce the chronic inflammation associated with obesity by modulating the activity of immune cells not only in adipose tissue but also within muscle tissue [139, 140]. Regular moderate exercise has been observed to shift the overall immune response toward a more anti-inflammatory state, which is generally considered beneficial in the context of many chronic diseases [141, 142]. This suggests that the positive effects of exercise on metabolic health are at least partly mediated by its ability to influence immune cell function and reduce systemic inflammation.

Cardiovascular diseases, a leading cause of morbidity and mortality worldwide, have also been linked to chronic inflammation. Epidemiological evidence indicates that regular physical activity is associated with a reduced incidence of cardiovascular disease [143]. Exercise has been shown to improve vascular function and contribute to the reduction of blood pressure [144]. It is plausible that the benefits of exercise for cardiovascular health are, in part, attributable to its capacity to regulate immune responses and lower the levels of systemic inflammation [143].

Beyond metabolic and cardiovascular conditions, exercise has also been implicated in the prevention and management of a wide range of other chronic inflammatory diseases and conditions, including certain types of cancer and autoimmune disorders. Exercise has been shown to enhance the body's immune surveillance mechanisms and can even improve the efficacy of vaccinations [145, 146]. These findings underscore the broad immunomodulatory effects of exercise, extending beyond its impact on muscle tissue and influencing a diverse array of systemic chronic diseases and immune responses [147, 148]. Therefore, physical exercise should be considered a fundamental lifestyle intervention for promoting overall health and reducing the burden associated with a wide spectrum of chronic diseases [149].

Repeated and sustained engagement in physical activity does more than provoke transient inflammatory responses—it leads to lasting immune remodeling that supports tissue repair, metabolic homeostasis, and disease resilience. Long-term exercise training has been shown to reduce the proportion of pro-inflammatory monocytes and increase regulatory T cells in both peripheral circulation and muscle tissue [148, 150, 151]. Chronic endurance training may also lower muscle-resident pro-inflammatory macrophage content while enhancing M2-like macrophage prevalence, contributing to a regenerative and anti-inflammatory muscle microenvironment [152–154].

On a systemic level, regular moderate-intensity exercise lowers markers of chronic inflammation, improves innate immune surveillance, and enhances adaptive immune responses in aging populations [145, 155]. These adaptations may be partially mediated by sustained upregulation of myokines such as IL-6 and IL-15, which influence immune cell trafficking, activation, and memory formation [156, 157].

Emerging evidence suggests that immune system “training,” akin to the concept of trained immunity or immunological memory, may also apply to exercise. Repeated bouts of muscle-damaging exercise reduce inflammatory responses and accelerate recovery—a phenomenon known as the repeated bout effect—and may involve the priming of innate and adaptive immune populations such as macrophages and T cells [158–160].

Despite these insights, many questions remain. The molecular signatures of long-term immune adaptation to exercise are still incompletely characterized. It is unclear how different types of training (resistance vs. endurance), frequency, and intensity affect the trajectory of immune remodeling, especially in populations with chronic disease or immunosenescence. Longitudinal studies and multi-omics approaches will be crucial in defining how exercise reprograms the immune system over time and how this contributes to lifelong musculoskeletal and systemic health.

Research gaps and future directions

While significant progress has been made in understanding the impact of exercise on immune cell infiltration in muscle tissue, several key research gaps remain that warrant further investigation. The specific roles of different lymphocyte subsets, particularly various memory T cell populations (e.g., CD4 + memory, CD8 + memory, resident memory T cells), in the context of muscle repair and adaptation following exercise still require more detailed elucidation. Furthermore, the precise mechanisms by which T cells contribute to the repeated bout effect, the phenomenon of reduced muscle soreness and damage with subsequent exercise, need to be more fully understood.

A significant portion of current knowledge is derived from studies examining the acute responses to exercise. More longitudinal studies are needed to comprehensively understand the long-term effects of various exercise regimens on immune cell infiltration and activity within muscle tissue, especially in the context of chronic diseases and the aging process [161]. Additionally, the influence of factors such as training status, exercise intensity, and duration on these immune responses needs further clarification.

A comprehensive understanding of the complex molecular mechanisms and signaling pathways that govern the recruitment, activation, and polarization of immune cells within muscle tissue in response to exercise is still an area of active investigation. Further research is needed to clarify the intricate interplay between different signaling molecules, including various cytokines, chemokines, and ATP [89].

The role and dynamics of resident immune cells within skeletal muscle and how exercise specifically affects these cells is another area requiring more attention. Understanding the interactions between these resident immune populations and the infiltrating immune cells during muscle repair following exercise is also crucial.

Translating the knowledge gained from exercise immunology into practical therapeutic strategies for preventing and managing chronic muscle diseases and other systemic conditions represents a promising avenue for future research. Identifying the optimal exercise protocols and intensities tailored to specific conditions is a crucial step in this direction.

Finally, future research should increasingly leverage multi-omics approaches, integrating data from genomics, transcriptomics, proteomics, and metabolomics, to achieve a more comprehensive understanding of the complex interactions between exercise, immune cells, and muscle tissue. This integrated approach promises to provide a more holistic view of the molecular changes that occur in response to exercise and their impact on immune function and muscle health.

In addition to circulating immune cells recruited to damaged muscle, resident immune populations—such as tissue-resident macrophages, muscle-resident memory T cells, and innate lymphoid cells (ILCs)—are increasingly recognized as important contributors to local immune regulation and tissue homeostasis [162, 163]. These cells may act as sentinels, initiating early responses to exercise-induced stress and interacting with infiltrating leukocytes to shape the inflammatory and regenerative milieu. However, the functional dynamics, tissue specificity, and exercise-induced modulation of resident immune cells remain largely unexplored. This represents a promising direction for future work, particularly given the potential for resident memory T cells to mediate ‘trained immunity’ and adaptive responses during repeated bouts of exercise [164, 165]. A deeper understanding of these cells may offer new insights into how long-term exercise reshapes immune memory, promotes efficient muscle regeneration, and supports systemic health.

Another underexplored area is the influence of biological sex, training history, and genetic predisposition on immune responses to exercise. Women and men exhibit distinct immune profiles, with differences in leukocyte subsets, cytokine responses, and inflammatory resolution kinetics following exercise [166, 167]. These sex-based variations may influence susceptibility to overtraining, recovery capacity, and long-term adaptation, particularly in aging populations or those with chronic conditions. Similarly, an individual’s prior training status can modulate immune plasticity, as well-trained individuals often display blunted inflammatory responses and enhanced regenerative signaling compared to untrained counterparts [168, 169]. Genetic factors further shape immune responsiveness through polymorphisms in cytokine genes, mitochondrial function regulators, and immune receptors [170, 171]. Future studies should stratify findings by sex and training background and investigate genetic contributions to better tailor exercise prescriptions for immunomodulation and tissue regeneration.

Conclusion

In conclusion, physical exercise profoundly impacts the infiltration of immune cells into muscle tissue, setting in motion a carefully orchestrated sequence of events critical for muscle repair and adaptation. The inflammatory response, initiated by neutrophils and amplified by pro-inflammatory M1 macrophages, plays a vital role in clearing cellular debris and signaling the subsequent regenerative phase. The transition to anti-inflammatory M2 macrophages is equally crucial, as these cells resolve inflammation, stimulate the differentiation and fusion of myoblasts, and facilitate the remodeling of the extracellular matrix. Furthermore, emerging evidence highlights the significant involvement of lymphocytes, particularly T cells, in muscle adaptation and the potential contribution of immunological memory to the repeated bout effect. These processes are governed by a complex interplay of signaling pathways involving cytokines, chemokines, and ATP, all of which are modulated by the mechanical and metabolic stresses of exercise [87].

The influence of exercise on immune cell infiltration in muscle extends to chronic muscle diseases such as sarcopenia, muscular dystrophy, and inflammatory myopathies, often exhibiting an anti-inflammatory effect and potentially offering therapeutic benefits. Moreover, the immunomodulatory effects of exercise have far-reaching implications for systemic chronic diseases, including metabolic and cardiovascular disorders, as well as other inflammatory conditions.

Despite the significant advances in our understanding of exercise immunology and muscle physiology, several key research gaps remain. Future investigations should focus on elucidating the specific roles of different lymphocyte subsets, conducting more longitudinal studies to assess long-term adaptations, further unraveling the complex molecular mechanisms of immune cell recruitment and polarization, exploring the role of muscle-resident immune cells, and translating these findings into targeted therapeutic interventions. The increasing use of multi-omics approaches promises to provide a more comprehensive understanding of the intricate interactions between exercise, the immune system, and muscle tissue. Continued research in this dynamic field holds immense potential for optimizing exercise strategies to enhance muscle repair, prevent and manage chronic muscle diseases, and promote overall health and well-being.

Author contributions

Yiping Su, Zhanguo Su involved in the conception, design, and drafting of the manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

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Consent for publication

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Clinical trial number

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