Indian Journal of Rheumatology

: 2020  |  Volume : 15  |  Issue : 6  |  Page : 99--111

Pathogenesis of muscle weakness in inflammatory myositis

Sai Kumar Dunga1, TG Sundaram2, Chengappa G Kavadichanda1,  
1 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Correspondence Address:
Dr. Chengappa G Kavadichanda
Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry


Idiopathic inflammatory myositis (IIM) is a heterogeneous group of autoimmune diseases. These are characterized by muscle weakness and fatigue along with other systemic manifestations, ranging from pulmonary alveolitis to vasculopathic ulcers. Muscle weakness is encountered in a majority of individuals with IIM. Several hypotheses for muscle weakness have been proposed, but none have been convincingly proven. Understanding of the pathophysiology of muscle weakness is necessary to better delineate therapeutic options and tailor exercise regimens in patients with IIM. In this review, we have attempted to delineate the immune and nonimmune pathways implicated in muscle weakness and integrated them with the clinical, histopathological, and imaging findings in IIM.

How to cite this article:
Dunga SK, Sundaram T G, Kavadichanda CG. Pathogenesis of muscle weakness in inflammatory myositis.Indian J Rheumatol 2020;15:99-111

How to cite this URL:
Dunga SK, Sundaram T G, Kavadichanda CG. Pathogenesis of muscle weakness in inflammatory myositis. Indian J Rheumatol [serial online] 2020 [cited 2021 Feb 26 ];15:99-111
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Full Text


Idiopathic inflammatory myositis (IIM) is a group of immune-mediated diseases, which includes polymyositis (PM), dermatomyositis (DM), sporadic inclusion body myositis (sIBM), immune-mediated necrotizing myositis, and overlap myositis. All these subgroups have skeletal muscle weakness and fatigue as a common feature in varying intensities. Besides muscle involvement, IIM also presents with extramuscular features such as skin lesions, arthritis, alveolitis, interstitial lung diseases (ILD), vasculopathy/vasculitis, fever, and other systemic manifestations. Like all acquired autoimmune diseases, IIM appears to occur in genetically predisposed individuals, following a “second hit” like an infection or a toxin.[1] Clinicians familiar with managing myositis recognize that muscle weakness in IIM can be attributed to active disease, steroid-induced myopathy, fibrosis, or fatty replacement of muscle fibers or due to coexisting endocrinopathies. Muscle biopsy from patients, primary human skeletal muscle tissue cultures, and disease modeling in different animals have turned out to be powerful and valuable tools to understand the complex pathophysiology of IIM. The ultimate goal of understanding the mechanisms involved in muscle weakness is to develop specific novel therapeutic targets based on the aberrant pathologic pathways, rather than the nonspecific immunosuppressive that are currently used. Further, understanding the pathways causing muscle weakness can allow clinicians to plan strategies to alleviate muscle damage and improve quality of life for patients suffering from these debilitating muscle diseases. In this review, we present the current evidence with an attempt to explain muscle weakness as a result of active disease in IIM.

 Search Strategy

A MEDLINE search was done for the MeSH terms “pathogenesis,” “etiology,” “muscle,” “weakness,” and “myositis” in different combinations. Relevant articles were screened, and their bibliography was manually checked for pertinent cross references. Although based on the available evidence, the review presents the authors' interpretation and also includes suggestions from the reviewers.

 Development of Muscle Tissue, Anatomy of Muscle Fiber, and Physiology of Power Generation

Before we attempt to understand the pathological processes involved in muscle weakness, the basic understanding of the muscle ultrastructure and its functioning is essential. Muscle cells originate from paraxial mesoderm which differentiates to myoblasts. The myoblasts fuse into multinucleated muscle fibers called myotubes. Myotubes, under the influence of transcription factors such as myocyte enhancer factor 2, form satellite cells, several bundles of which constitute mature muscle fibers.[2] These muscle fibers form the basis of skeletal, smooth, and cardiac muscles. Skeletal muscles appear striated because of the difference in refractive indices, resulting from the characteristic arrangement of cytoskeletal proteins: actin and myosin.

Combination of cytoskeletal proteins results in the formation of sarcomeres, which are the building blocks of muscle fibers. A sarcomere [Figure 1]a is comprised of thick and thin filaments. Thick filaments are predominantly made of myosin and thin with actin [Figure 1]b. While myosin is the main force generator in muscles, actin is the predominant component of thin filaments, along with troponin and tropomyosin [Figure 1]c. Troponin and tropomyosin regulate the binding of myosin head to actin, in the presence of calcium [Figure 2].[3],[4] The calcium store is found within the sarcotubular system, which are a network of membranes in the striated muscle fibers. They are formed by two tubular structures namely the transverse tubules and cisternal formations [Figure 1]d. Cisternal formations and transverse tubules are placed at proximity and are linked to each other by longitudinal tubules [Figure 1]d.[4] There are different types of skeletal muscle fibers, namely the Type I, IIa, IIB, and IIC. These fibers are classified based on their function and energy utilization mechanism.[5] In IIM, their involvement is variable. Details about these muscle fibers are presented in [Table 1].{Figure 1}{Figure 2}{Table 1}

Muscle contraction is explained by the sliding filament theory,[6] which states that the cytoskeletal structures of muscles rearrange and form cross-bridges in the presence of calcium and adenosine triphosphate (ATP).[7] The contraction–relaxation cycle generates power, and the steps are depicted in [Figure 2]. [Figure 2] also represents a simplistic view of how several factors in IIM contribute to muscle weakness by affecting each of the steps in the contraction cycle. To understand these changes in IIM, we will first examine the evidence for skeletal muscle involvement in IIM starting with the clinical findings and then progressing to examine the histopathological, metabolic, and radiographic evidence. We then describe the various immunological and nonimmunological bases for these changes with evidence from several studies.

 Microvascular and Muscle Fiber Insult Resulting in Muscle Fiber Degeneration

Learning from clinical experience

In IIM, beyond overt muscle weakness, we often encounter myalgia, effort intolerance, subcutaneous edema, and skin lesions. Effort intolerance in myositis seems to be mainly due to microvascular dysregulation and defective energy production by the mitochondria. Similarly, cutaneous and internal organ ulcers also point to a marked involvement of microvasculature in IIM. In addition to these, nail-fold capillaroscopic observations have shown capillary rarefaction in both DM and PM and changes correlate significantly with muscle weakness, suggesting a close link between microvascular dysfunction and muscle weakness.[8],[9]

Histopathological examination of involved skeletal muscles show variable degrees of necrosis, inflammatory infiltrate, regeneration, and degeneration of muscle fibers and also confirms the suspicion of microvascular dysfunction. Perifascicular muscle fiber atrophy specifically involving Type IIA fibers is often encountered along with vasculopathy in DM.[10],[11] Skeletal muscle biopsies also show thickening and obliteration of the blood vessel lumen in the perimysium along with perivascular lymphocyte infiltration.[12] Children with Juvenile dermatomyositis (JDM) seem to exhibit most changes in the muscle vasculature.[13] In a study on 50 patients with DM, review of muscle biopsies showed a 2-fold reduction in the capillary density and 3-fold reduction in the transverse vessel density. The same study also found marked capillary loss in those with late and untreated disease as compared to patients who were on adequate treatment and those with mild muscle weakness.[14] Morphometric and immunohistochemical studies have further identified early decrease in capillary density before the onset of perifascicular atrophy.[15] These findings were confirmed in ultrastructural studies which showed abnormalities in the endothelial cells of capillaries, arterioles, and veins[16] of patients with IIM, even in patients with intact muscle fibers. Other noticeable finding is the preferential loss of endothelial markers, PECAM-1, UEA lectin staining, and VE cadherin in the endothelial cells adjoining the perifascicular atrophic areas[17] in the muscle. Although these changes are more pronounced in DM, studies on PM have also shown capillary rarefaction and clumping of endothelial cells.[18] Thus, it is apparent that microvascular dysfunction and muscle damage are closely interlinked, and the biopsy evidence suggests that the former may precede muscle fiber damage.

Imaging evidence also seems to reflect the story of microvascular dysfunction followed by muscle inflammation and muscle fiber loss. Although ultrasonography and magnetic resonance imaging (MRI) do not directly tell us about the pathophysiological process, they give a fair idea of the anatomy of the muscle and its surrounding tissues. Power Doppler ultrasound has demonstrated early fasciitis in DM, which is due to leaky vessels in the muscle fascia.[19] A recent MRI study confirmed the above findings. The investigators detected edema in the fascia covering the muscles early in the disease course, again suggesting that the microvasculature around the fascia to be the primary target of the inflammation.[20] Besides this, MRI commonly shows muscle edema in cases of active IIM. Although this is a nonspecific sign and can also be seen in noninflammatory conditions such as acute subacute denervation, interstitial fluid overload, and trauma,[21] biopsies from these sites have shown inflammatory infiltrates and other classical features of IIM. Although the degree of muscle edema and fatty replacement correlate with the magnitude of muscle weakness, these findings seem to appear only after the edema at the muscle fascia. From all this, it seems that the vascular disturbance and energy distribution mechanisms are initial clinically detectable involvement in myositis and could possibly be occurring much earlier in the diseases course. What causes this involvement is still not clear, but it seems to be a combination of immune and nonimmune mechanisms.

Immune activation

The pathways that trigger immune response in IIM are common to various pathophysiological processes, inducing muscle weakness. These immune pathways once triggered can result in damage to muscle fibers, impair regeneration of the damaged muscle fibers, decrease contractility, and upregulate nonimmune pathways.

In an individual with genetic susceptibility, disease can be triggered secondary to various environmental exposures such as respiratory infections, viral infections, toxins, and drugs. These exposures result in release of damage-associated molecular patterns (DAMPs) and presentation of pathogen-associated molecular patters along with other antigens. Such exposures can trigger innate and adaptive immune system, leading to inflammation and autoimmunity. Following this, damaged muscle fibers undergo degeneration and regeneration. In the process of regeneration, these immature muscle fibers overexpress HLA class I antigens and Toll-like receptors (TLRs) and release various myositis-specific antigens and DAMPs.[22] Evidence from biopsies in PM and DM has shown overexpression of TLR-3 and TLR-7, with differential regulation by T helper 1 (TH1) and TH17 cytokines at the site of inflammation.[23] Besides this, overexpression of high mobility group box chromosomal protein 1 (HMGB-1), an endogenous TLR ligand, is also increased in muscle tissues in IIM.[24] The muscle enzyme creatine kinase which is released as a result of muscle damage also behaves as an endogenous TLR ligand. Activation of TLRs by these endogenous ligands results in MyD-88 signaling cascade, culminating in the nuclear factor kappa B (NF-κB) activation.[25] The activation of NF-κB results in increased production of several inflammatory cytokines, including interferon (IFN)-γ, interleukin (IL)-12, p40, and IL-17. NF-κB signaling also results in immune cell recruitment into a milieu that is ripe for antigen processing and presentation. These immune cells and cytokines can further activate TH1, TH17, TH2, CD8+ cytotoxic T-cells and CD28null T-cells, an event which seems to trigger activation of the adaptive immune system.[26] These mechanisms are not specific for IIM and are a general overview into immune activation. DAMPs such as HMGB-1 are also implicated in other diseases such as lupus but in the context of IIM have specific implications on muscle fibers. In the innate immune dysregulation, neutrophils have been implicated as major contributors to muscle damage.

Microvascular damage in idiopathic inflammatory myositis

In early disease, Type 1 IFN and the IFN-responsive elements seem to mediate microvascular changes.[27] IFN is primal to vessel health, and dysregulated IFN production is associated with endothelial damage and clumping which is suggested by the presence of noninflammatory occlusive vasculopathy and capillary loss[28] in IIM. The complement pathway also appears to play a major role in the endothelium damage, and C5b9-complement component is detected on the damaged endothelium in the necrotic endothelium.[17] This further strengthens the links between microvascular dysfunction and loss of muscle fibers, eventually resulting in muscle weakness. Thus, innate immune response is implicated in precipitating the pathogenesis of myositis and neutrophils are mainly implicated.

Role of neutrophils in muscle damage

Neutrophil extracellular traps (NETs) have been recently studied in IIM. Circulating NETs and low density granulocytes (LDGs), which are increased in IIMs, also correlate with disease activity mainly Manual muscle testing 8 (MMT-8).[29] The levels of NET formation also correlates with the levels of autoantibodies such as anti-MDA5, thus implicating the role of NETs in excess presentation of self-antigens.[30] NETs also are found to decrease myotubule viability.[29] This impairment is possibly mediated through elastase and citrullinated histone. Elastase-mediated myotubule toxicity is irreversible, whereas citrullinated histone-mediated toxicity is reversible,[29] implying its effects on muscle weakness. The exact mechanisms how citrullinated histone causes myotubule toxicity are unclear, but it seems to be a combination of TLR-mediated immune pathway activation and upregulation of nonprogrammed cell death processes.[31]

Major histocompatibility complex class I upregulation and its implication in muscle damage

Major histocompatibility complex (MHC) is downregulated in myoblasts, myotubes, and mature muscle cells under healthy conditions.[32] Immunohistochemical studies in myositis have shown widespread upregulation of MHC-I in muscle fibers.[33] Evidence from studies in a mouse model suggests a phenomenon of spontaneous development of myositis upon conditional upregulation of MHC-I in the muscle fibers. The disease in this model is strikingly similar to myositis in humans with inflammation in the skeletal muscles, often associated with autoantibodies to histidyl-tRNA synthetase (Jo-1).[33] MHC-I overexpression in IIM is responsible for CD8 T-cell activation and in precipitating endoplasmic reticular stress, both of which causes muscle weakness.

Adaptive immune mechanisms and muscle damage

Role of adaptive immune system in IIM is evident due to the presence of several myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs). The process of adaptive immune involvement seems to start due to innate immune activation, as discussed in the earlier section. Further, the strong genetic risk association of IIM with several MHC genes including the 8.1 ancestral haplotype, HLA-B*08:01, DQB1* 02:01, and DRB1* 03:01 favors the role of adaptive immune system in diseases pathogenesis.[34]

Direct damage of muscle fiber by cytotoxic T-cells

Based on immunohistochemistry of muscle biopsies, CD4+ T-cells are mainly implicated in DM and CD8+ T-cells in PM.[35] While the distribution of perforin is random in the cytoplasm of T-cells that infiltrate the muscle fibers in DM, it has vectorial orientation toward a muscle fiber in PM.[36] This again suggests that CD8 T-cell activation in DM is nonspecific but in PM is directed against specific antigens on the muscle fiber. Apart from PM, CD8+ T-cells are found in nonnecrotic muscle fibers in IBM.[37] The cytotoxic T-cells are highly differentiated and express the killer cell lectin-like receptor G1.[38] It has been shown that muscle apoptosis is mediated by perforin-mediated cytotoxicity.[39]

CD28 (null) T-cells are a subset of T-cells infiltrating muscle fibers in both DM and PM, which are long-lived, terminally differentiated, and resistant to apoptosis.[40] Role of FOXP3+ T-regulatory cells are still unknown in IIM, but studies have shown that they are found in higher numbers and in proximity to effector cells,[41] indicating a possibility of loss of functionality in these regulatory cells.

B-cell-mediated mechanisms

Although the role of B-cells and plasma cells in instigating muscle damage in myositis is not directly evident, their role seems to be important as they are responsible for the production of MSAs or MAAs. These antibodies are seen in 65%–70% of patients with IIM.[42] MSAs target ubiquitously expressed intracellular antigens, which are essential for cellular processes, such as gene regulation, transcription, and translation.[42] Besides this, B-cells also act as antigen-presenting cells to T-cells and further aid in T-cell-mediated damage. Specific immune responses against antigens such as Jo-1 in animal andin vitro studies have demonstrated their role in muscle inflammation.[43] B-cell-targeted therapy, especially in anti-Mi2 and anti-Jo-1 autoantibody-positive individuals, have shown improvement in muscle weakness, which correlated with fall in antibody titers.[44] The autoantibodies directed against anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and anti-signal recognition particle impair muscle regeneration by reducing the cytokines necessary for myotubule differentiation.[45] Besides, decreased levels of B-regulatory cells are also identified in DM and their levels inversely correlate with the presence of MSAs and ILD,[46] thus implicating an MSA-independent mechanism role of B-cells in the pathogenesis of muscle weakness. However, the information is sketchy and needs further studies to convincingly prove the role of B-cells and plasma cells in causing muscle weakness.

Cytokines and myokines

Cytokines are necessary for intracellular message transfer. Their release can be due to both innate and adaptive immune activation. The role of each implicated cytokine in muscle weakness is tabulated in [Table 2]. Some cytokines such as tumor necrosis factor (TNF)-like weak inducer of apoptosis and YinYang1 [Table 2] inhibit mesoangioblasts and impair repair of damaged muscle fibers, thus preventing effective muscle regeneration. Another group of muscle-specific cytokines are the myokines. Myokines are released in response to muscle contractions.[66] They are implicated in muscle growth and metabolism. Apart from this, they induce expression of inflammatory cytokines and MHC-I in IIM.[67],[68],[69] Myokines can cause muscle weakness by paracrine signaling and effect adjacent muscle fibers through nonimmune cell-mediated mechanisms, such as endoplasmic reticulum (ER) stress pathway activation.[70],[71] The prototype myokine, myostatin is a negative regulator of muscle cell differentiation and growth, thereby leading to inhibition of myogenesis.[72] Hence, several mechanisms targeting myostatin and monoclonal antibodies targeting its receptor activin type IIB receptor, receptor decoys, and follistatin were experimented in various clinical trials.[73] Drug trials targeting myostatin pathway with stamulumab were not successful in demonstrating[74],[75],[76] improvement in muscle strength but showed marginal benefits in a few small open-label studies on Becker muscular dystrophy and IBM,[77],[78],[79] thus challenging out current understanding of the myostatin pathway in IIM.{Table 2}

Several studies have also shown that IL-1 is expressed on the endothelial cells remote from inflammatory focus, suggesting its role as a potential initiator of endothelial dysfunction.[47],[48],[49] Similarly, IFN increases TLR3 signaling in the endothelial cells implicating a role in vasculopathy.[56],[57],[80] Apart from cytokines, ELR-negative CXC chemokines which are angiostatic are expressed at higher level in JDM. The levels ELR-negative CXC chemokine expression correlates with the magnitude of mononuclear cell infiltration and capillary loss.[81]

Nonimmune mechanisms of muscle damage

Endoplasmic reticulum stress

As already mentioned, MHC-I upregulation in the muscle tissue is an important initial step, resulting in muscle damage. There is evidence that, apart from activating inflammatory pathways, MHC-I also induces ER stress.[33] ER is the site in which MHC proteins are synthesized and folded properly, and when MHC-I upregulation occurs, there is increased chance of misfolding of MHC-I proteins. ER stress is also precipitated by reactive oxygen species (ROS) released as a result of mitochondrial dysfunction and intracellular calcium imbalance. Once ER stress is initiated, it culminates into either of the two adaptive mechanisms; the unfolded protein response (UPR) and the ER-overloaded response.[82]

The UPR activates three ER membrane-associated proteins: inositol requiring enzyme 1, PKR eukaryotic initiation factor-like kinase 2, and activating transcription factor 6.[83] Under normal conditions, GRP78 and GRP94 chaperones keep the ER stress under control. In UPR, there is upregulation of these chaperones, with the acceleration of protein packaging in the ER and slowing down of translation and protein synthesis, thus preventing further ER stress. ER stress also results in overexpression and colocalization of homocysteine-induced ER protein (Herp) with GRP94, which has a protective mechanism and enhances packaging ability of ER, contributing to ER-associated degradation.[84] In sIBM, Herp is induced in muscle fibers under stress along with beta-amyloid and GRP78.[84] When UPR is overwhelmed, the cell switches to overload response, resulting in NF-κB activation.[85] When the above compensatory mechanisms are overwhelmed, the muscle cells undergo apoptosis.[82] Muscle biopsies in IIM shows overexpression of GRP94 and GRP75. While GRP94 overexpression was observed specifically in regenerating muscle fibers, GRP75 and calreticulin were found in all the MHC-I-expressing myofibrils.[86] ER stress also acts as a negative regulator of muscle growth via aggregation of myostatin precursor protein.[87]


Autophagy is the lysosomal degradation of a cell's own proteins or organelles. Sequestered cytoplasmic material is packed in double membrane structures called autophagosomes, which then fuse with the lysosomes and are degraded. Autophagy-related proteins assemble into functional complexes, which are activated and recruited to membranes to initiate autophagy.[80] Muscle biopsies in PM and sIBM have consistently shown higher expression of autophagosome marker, LC3-II. On the other hand, protein aggregates such as amyloid-β and phosphorylated tau, which in normal conditions are degraded by lysosomes, are increased in sIBM suggesting a possibility of defective autophagy.[88]

In IIM, autophagy seems to be induced by cytokines such as TNF[80] and TNF-related apoptosis-inducing ligand,[89] leading to muscle cell death. Studies have demonstrated colocalization of TLR-3 and TLR-4 with LC3, suggesting a potential link between autophagy and innate immune response.[80] The myodegeneration is characterized by the impairment of autophagy with findings such as rimmed vacuoles and the presence of LC3-, p62-, and TDP-43-positive sarcoplasmic aggregates of sIBM. It is likely that, in IIM, inflammation is the inciting event and later muscle degeneration by mechanisms such as autophagy take over.[90]

Role of microRNA

MicroRNAs regulate cell differentiation and proliferation, growth, and apoptosis. Specific group of microRNAs abundant in the skeletal muscles are known as myomiRs, which have a reciprocal relationship with regulatory factors of myogenesis.[91] For instance, studies have shown upregulation of miR-146b, miR-221, miR-155, miR-214, and miR-222[92] and downregulation of miR-1, miR-206, and miR-133a/b in IIM,[93] showing yet another unexplored area in the understanding of IIM.

 Muscle Cross-Bridge Failure

Besides structural derangement in the muscle fibers as a consequence of necrosis, apoptosis, and impaired regeneration, functional impairment also plays a significant role in muscle weakness. Some of the mechanisms resulting in functional impairment of muscle contraction may overlap with the previously mentioned pathways. The predominant pathways are the impairment in calcium regulation within the sarcoplasmic reticulum (SR) and mitochondrial dysfunction. Disturbance in these pathways though causes muscle cross-bridge failure initially, they will eventually lead to muscle damage.

Evidence from 31-phosphate (P)-magnetic resonance spectroscopy (MRS) studies have shown that the changes metabolites which correlate with the regeneration and degeneration of muscle fibers.[94],[95] In IIM, 31P-MRS demonstrated variations in muscle energy metabolites such as inorganic phosphate, phosphocreatine (PCr), ATP, phosphodiesters, and pH before and after exercise.[21],[96],[97] In adults with PM/DM, levels of PCr and ATP were reduced at resting state, and these findings were further exacerbated following exercise.[98] This reflects overall low-energy state possibly due to compromised vasculature or due to abnormal mitochondrial function in myositis. The changes detected were not only in those who had overt muscle weakness but also among the amyopathic individuals with IIM, suggesting that the energy imbalance occurs much before the onset of overt muscle weakness. Besides, the metabolic parameters improved with improvement in diseases activity, confirming that energy imbalance closely reflects the underlying mechanisms involved in causing muscle weakness.[20] Important aspect of these findings are that these changes were found in muscle groups which had normal architecture, thus suggesting a role of other factors such as ROS and mitochondrial dysfunction in preventing cytoskeletal cross-bridge formation.

Role of damage-associated molecular patterns and reactive oxygen species

As mentioned earlier, HMGB-1 is overexpressed on muscle fibers in IIM. HMGB-1 acts as an endogenous TLR ligand and activates the NF-κB pathway. NF-κB activation results in release of several inflammatory cytokines, which result in poor muscle contraction [Table 2]. Besides acting as an endogenous TLR ligand, exposure of HMGB-1 to muscle fibers also causes decreased calcium release from the SR. This decreases affects binding of myosin to actin[99] and thus leads to failure of cross-bridge formation.

Alteration in calcium homeostasis is mainly implicated in the pathogenesis of IBM. In healthy skeletal muscle fibers, several mechanisms maintain a low resting intracellular calcium concentration. When this regulation is perturbed, prolonged cytosolic Ca[2+ elevations can cause various downstream myodegenerative phenomena. It causes abnormal proteostasis by promoting mitochondrial ROS production and altering protein folding in ER ultimately, resulting in muscle fiber degeneration.[100]

ROS are also generated during oxidative metabolism and oxidative burst in granulocytes as cellular response to hypoxia, cytokines, or pathogens.[101] ROS such as superoxide anion (O2−) and hydrogen peroxide cause contractile dysfunction in the muscle fibers and in turn muscle weakness.[102] Several cytokine and myokines have been shown to generate ROS in the skeletal muscle,[103] possibly contributing to muscle dysfunction.[104]

Mitochondrial disturbance

Mitochondria, the power house of the cell, provide ATP required for muscle contraction. Evidence suggests that dysregulated mitochondrial functions[105] such as abnormalities in succinate dehydrogenase and cytochrome c oxidase are seen in atrophic, perifascicular muscle fibers of DM.[106] Deficiency of the enzyme, AMP deaminase 1 (AMPD1), has been shown to cause disruption of ATP metabolism and cause muscle weakness in animal studies.[107],[108] AMPD1 is an enzyme, specifically present in Type 2 muscle fibers, a group that is predominantly affected in inflammatory myositis. In mice, AMPD1 deficiency correlated with muscle weakness and the metabolic disturbance. The muscle weakness was detected before infiltration by mononuclear cells,[108] suggesting that muscle involvement due to mitochondrial dysfunction may occur before inflammation. A recent animal study has shown upregulation of mitochondria-localized activator of apoptosis-harakiri (HRK) in myositis. Levels of HRK expression seem to inversely determine mitochondrial potential and ability to repair, following injury to muscle.[109] Hence, the overall evidence seems to point to dysfunction in mitochondria occurring before the onset of inflammation, which leads to decreased ATP and ultimately results in death of muscle fibers, contributing to muscle weakness.

 Understanding Pathophysiology from Response to Treatment and Exercise

Pathophysiology of muscle weakness can also be understood by looking at benefits with various therapeutic strategies and the association of biomarkers with improvement in muscle strength. The improvement in muscle weakness with glucocorticoids, intravenous immunoglobulin, and various other immunosuppressive agents re-emphasizes the role of immune dysregulation and inflammation in myositis. Several studies elucidating clinical improvement and the molecular basis of benefits from exercise in IIM have been published.[110],[111],[112],[113],[114] Gene expression patterns reflect tilted balance in favor of anti-inflammatory genes in association with clinical improvement. Prostaglandin-endoperoxide synthase 1 gene is persistently upregulated in patients with refractory weakness[115] but is reduced with physical training. The reduction is followed by a upregulation of FOXP3 and a downregulation of SMAD7-dependent signaling. These results suggest a reciprocal alteration of T-cell activity toward a regulatory phenotype and downregulation of fibrosis and damage with exercise.[116] Study on muscle biopsy postresistance exercise for 7 weeks showed decrease in the serum C1q levels; decreased transforming growth factor (TGF-β) signaling along with TGF-β 1R, connective tissue growth factor, and fibroblast growth factor; and increased expression of latent-TGF beta-binding protein.[96] This evidence suggests a role for exercise in preventing muscle damage and fibrosis, through the TGF-β pathway. Exercise also suppresses synthesis of collagen and other Extracellular matrix (ECM) components. It also increases breakdown of collagen by matrix metalloproteinases (MMPs), such as MMP-16.[115] Treatment with glucocorticoids and exercise also shifts muscle metabolic genes toward energy-efficient oxidative profile, thus possibly reversing the mitochondrial dysfunction. Exercise in IIM also increases mitochondrial enzymes such as citrate synthase and β-hydroxyacyl-CoA dehydrogenase.[117] Physical training in myositis is responsible for cytoskeletal remodeling and upregulation of genes that encode myosin IB, myosin VIIA, and actin-binding proteins and reduce ER stress.[118] These findings show that immunosuppression and physical training lead to the improvement in muscle function by altering the immune response, decreasing fibrosis, reversing mitochondrial dysfunction, and promoting muscle cytoskeletal development, all of which are known to be dysregulated during active disease.


The current-day understanding of pathogenesis of muscle weakness in IIM suggests an initial microvascular and mitochondrial dysfunction followed by innate immune activation at the muscles which perpetuates the adaptive immune response. There are also several nonimmune mechanisms such as ER stress and UPR which act in tandem with aberrant immune response and resulting in muscle weakness. The muscle weakness is a direct result of damage to muscle fibers, impaired regeneration mechanisms, and decreased cross-bridge formation. The above pathogenetic mechanisms are not mutually exclusive but are overlapping and interdependent [Figure 3]. Targeting a single pathway in myositis treatment may not be beneficial, and there is a dire need of new therapeutic strategies that target, innate, adaptive, and metabolic pathways. Although our understanding is grossly incomplete, research in IIM is catching up at an optimistic pace which will undoubtedly translate to better outcomes in this rare disease.{Figure 3}

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