Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell­ and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFß1). Blocking TGFß signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell­stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

Atypical skin conditions of the neck and back as a dermal manifestation of anti-HMGCR antibody-positive myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is an idiopathic inflammatory myopathy (IIM). Though patients with IMNM were not considered to show skin rash, several reports have showed atypical skin conditions in patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-positive IMNM (HMGCR-IMNM). The incidence and phenotype of skin conditions in patients with HMGCR-IMNM are not fully known. RESULTS: Among the 100 IIM patients diagnosed from April 2015 through August 2022, 34 (34%) presented some form of skin condition, with 27 having typical skin rashes; this included 13 patients with dermatomyositis (DM), 8 with anti-synthetase syndrome (ASS), and 6 with IMNM. Meanwhile, 8 of 19 patients with HMGCR-IMNM (42%) presented atypical skin lesions, but no patients with other IIMs did (p < 0.001). Skin eruption with ash-like scales was observed in four HMGCR-IMNM patients, and non-scaly red patches and lumps in the other four patients; accordingly, their skin manifestations were considered as other dermal diseases except for IIM. However, skin and muscle biopsies revealed the atypical skin conditions of patients with HMGCR-IMNM to have the same pathological background, formed by Bcl-2-positive lymphocyte infiltrations. CONCLUSIONS: HMGCR-IMNM patients frequently have atypical skin conditions of the neck and back. Skin biopsy specimens from these lesions showed the same Bcl-2-positive lymphocytic infiltrations as muscle biopsy specimens regardless of the different gross dermal findings. Thus, such atypical skin conditions may be suggestive for HMGCR-IMNM.

Myeloid mineralocorticoid receptors contribute to skeletal muscle repair in muscular dystrophy and acute muscle injury.

Suppressing mineralocorticoid receptor (MR) activity with MR antagonists is therapeutic for chronic skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. Although mechanisms underlying clinical MR antagonist efficacy for DMD cardiomyopathy and other cardiac diseases are defined, mechanisms in skeletal muscles are not fully elucidated. Myofiber MR knockout improves skeletal muscle force and a subset of dystrophic pathology. However, MR signaling in myeloid cells is known to be a major contributor to cardiac efficacy. To define contributions of myeloid MR in skeletal muscle function and disease, we performed parallel assessments of muscle pathology, cytokine levels, and myeloid cell populations resulting from myeloid MR genetic knockout in muscular dystrophy and acute muscle injury. Myeloid MR knockout led to lower levels of C-C motif chemokine receptor 2 (CCR2)-expressing macrophages, resulting in sustained myofiber damage after acute injury of normal muscle. In acute injury, myeloid MR knockout also led to increased local muscle levels of the enzyme that produces the endogenous MR agonist aldosterone, further supporting important contributions of MR signaling in normal muscle repair. In muscular dystrophy, myeloid MR knockout altered cytokine levels differentially between quadriceps and diaphragm muscles, which contain different myeloid populations. Myeloid MR knockout led to higher levels of fibrosis in dystrophic diaphragm. These results support important contributions of myeloid MR signaling to skeletal muscle repair in acute and chronic injuries and highlight the useful information gained from cell-specific genetic knockouts to delineate mechanisms of pharmacological efficacy.

Anti-nuclear matrix protein 2 antibody-positive inflammatory myopathies represent extensive myositis without dermatomyositis-specific rash.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) define distinct clinical subsets of idiopathic inflammatory myopathies (IIMs). The anti-nuclear matrix protein 2 (NXP2) antibody, a MSA detected in juvenile/adult IIMs, has been reported to be associated with a high risk of subcutaneous calcinosis, subcutaneous oedema and internal malignancies. The study aimed to clarify the clinical features of anti-NXP2 antibody-positive IIMs in detail. METHODS: This was a multicentre retrospective observational study on 76 anti-NXP2 antibody-positive patients. The antibody was detected via a serological assay using immunoprecipitation and western blotting. The patients were selected from 162 consecutive Japanese patients with IIMs. RESULTS: The cohort of anti-NXP2 antibody-positive IIMs included 29 juvenile patients and 47 adult patients. Twenty-seven (35.5%) patients presented with polymyositis phenotype without dermatomyositis-specific skin manifestations (heliotrope rash or Gottron sign/papules); this was more common in the adults than children (48.9% vs 15.8%, P < 0.01). Nine (11.8%) patients had subcutaneous calcinosis, and 20 (26.3%) patients had subcutaneous oedema. In addition, the proportion of patients with muscle weakness extending to the distal limbs was high (36 patients [47.4%]) in this cohort. Adult patients had a higher prevalence of malignancy than the general population (age-standardized incidence ratio of malignancies: 22.4). CONCLUSION: Anti-NXP2 antibody-positive IIMs, which include dermatomyositis sine dermatitis, are characterized by atypical skin manifestations and extensive muscular involvement.

Differential Effects of Myeloid Cell PPARδ and IL-10 in Regulating Macrophage Recruitment, Phenotype, and Regeneration following Acute Muscle Injury.

Changes in macrophage phenotype in injured muscle profoundly influence regeneration. In particular, the shift of macrophages from a proinflammatory (M1 biased) phenotype to a proregenerative (M2 biased) phenotype characterized by expression of CD206 and CD163 is essential for normal repair. According to the current canonical mechanism regulating for M1/M2 phenotype transition, signaling through PPARδ is necessary for obtaining the M2-biased phenotype. Our findings confirm that the murine myeloid cell-targeted deletion of Ppard reduces expression in vitro of genes that are activated in M2-biased macrophages; however, the mutation in mice in vivo increased numbers of CD206+ M2-biased macrophages and did not reduce the expression of phenotypic markers of M2-biased macrophages in regenerating muscle. Nevertheless, the mutation impaired CCL2-mediated chemotaxis of macrophages and slowed revascularization of injured muscle. In contrast, null mutation of IL-10 diminished M2-biased macrophages but produced no defects in muscle revascularization. Our results provide two significant findings. First, they illustrate that mechanisms that regulate macrophage phenotype transitions in vitro are not always predictive of mechanisms that are most important in vivo. Second, they show that mechanisms that regulate macrophage phenotype transitions differ in different in vivo environments.

Cutaneous involvement in anti-HMGCR positive necrotizing myopathy.

OBJECTIVE: Anti-3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive immune-mediated necrotizing myopathy (IMNM) is a rare disease. It is induced by exogenous substances, most often by statins. Little is known about cutaneous manifestations of HMGCR positive IMNM and about HMGCR antibody positivity in other diseases. METHODS: The characteristics of patients with anti-HMGCR autoantibodies measured at our laboratory between January 2012 and September 2020 were studied. Characteristics of patients with IMNM were compared to those patients with positive antibodies but without muscle involvement. Associations of IMNM with other organ involvements were searched for. RESULTS: Of the 32 patients studied, 23 showed characteristics of IMNM, 9 did not fulfill current classification criteria but most showed signs of connective tissue diseases. Patients with IMNM were older (66 and 35 years, respectively; 0.92 (0.73-0.98); p < 0.001), had more frequent statin exposure (87% and 33%, respectively; 0.84 (0.61-0.94); p = 0.005) and higher mean peak CK (8717U/l and 329U/l, respectively; 1.0 (0.85-1.0); p < 0.001). 13/23 (56%) of IMNM patients showed cutaneous lesions; none of the patients suffered from cancer; only three IMNM patients showed drug-free complete remission. Incidence of IMNM in the catchment area of our center is at least 2.7/Mio/year. CONCLUSION: Cutaneous lesions were found to be more frequent in anti-HMRCR positive IMNM than previously reported. Titer of anti-HMGCR antibodies and CK levels were significantly higher in IMNM than in other autoimmune connective tissue diseases. The data support the hypothesis of an antigen-driven response in IMNM, and suggests an activation of autoreactive B-lymphocytes in non-IMNM patients.

Potential implications of six American Indian patients with myopathy, statin exposure and anti-HMGCR antibodies.

OBJECTIVES: Statin-associated autoimmune myopathy is a rare condition associated with the formation of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Underlying environmental and genetic risk factors remain poorly understood. American Indians have high rates of cardiovascular disease and associated co-morbidities that require lipid-lowering therapies. We observed this autoimmune myopathy in a series of American Indian statin users in rural Arizona. METHODS: We reviewed the charts of six American Indian patients with statin-associated autoimmune myopathy. We provide an illustrative case in addition to summaries of clinical presentations and treatment courses. RESULTS: This is the first report of statin-associated autoimmune myopathy in American Indians. These cases were all identified at the same geographically isolated hospital that exclusively serves an American Indian population with only 1800 statin users. There is relatively low migration. Each case was consistent with the previously described classical presentations for the disease. All six of our cases had diabetes and developed myopathy on high-dose atorvastatin, often with a recent change in statin type or dose. CONCLUSION: Providers serving American Indians need to be aware of the possibility of statin-associated autoimmune myopathy and familiar with its presentation. Larger, inclusive, population-based investigations are needed to elucidate risk factors for this condition, in particular the potential interactions between predisposing HLA alleles, diabetes and specific statin exposures. This is necessary to identify effective and safe lipid-lowering medications.

Alterations of macrophage and neutrophil content in skeletal muscle of aged versus young mice.

BACKGROUND: Skeletal muscle inflammation and oxidative stress are associated with aging-related loss of muscle mass and may be attributable to alterations in the number and types of leukocytes in skeletal muscle. Here, we tested the hypothesis that aging changes the number and composition of leukocyte subsets in skeletal muscle tissue. METHODS: Skeletal muscle was sampled from 4-mo-old (young) and 27-mo-old (old) C57BL/6J mice. Mononuclear cells of the gastrocnemius muscle were isolated, and flow cytometry was used to characterize the number and types of immune cells. RESULTS: The number of neutrophils and Ly-6C+ inflammatory macrophages in the skeletal muscle was significantly higher in old mice than in young mice. Inflammation and oxidative stress (measured using the markers phosphorylated JNK and nitrotyrosine) were also higher in the skeletal muscle of old mice than in that of young mice. CONCLUSIONS: Increasing age promotes skeletal muscle inflammation and oxidative stress, as well as infiltration of inflammatory macrophages and neutrophils.

Antigenicity of hypothetical protein HP33 of Vibrio harveyi Y6 causing scale drop and muscle necrosis disease in Asian sea bass.

A unique strain of Vibrio harveyi is the causative agent of scale drop and muscle necrosis disease (SDMND) in Asian sea bass (Lates calcarifer). This study investigated the protein profiles of SDMND-causing Vibrio harveyi isolates compared to the reference V. harveyi ATCC 14126 strain. A distinct protein band of 33 kDa, namely HP33, found from only V. harveyi SDMND was subjected to analysis by LC-MS/MS and the identified peptide sequences matched to an unknown hypothetical protein. Detection of HP33 coding sequence was investigated at both genomic and transcriptional levels and the results consistently supported the protein analysis. Recombinant HP33 protein was then produced using Escherichia coli system. The rHP33 protein did not cause mortality or visible clinical signs to Asian sea bass. However, the rHP33 protein was able to stimulate antibody response in Asian sea bass as evidenced by Western blotting and agglutination tests. Here, we proposed that rHP33 might be a good protein target for development of subunit vaccine and/or immunostimulant to protect Asian sea bass from SDMND.

Immunotherapy reversed myopathy but not cardiomyopathy in a necrotizing autoimmune myopathy patient with positive anti-SRP and MDA-5 autoantibodies.

BACKGROUND: Necrotizing autoimmune myopathy (NAM) is pathologically characterized by myofiber necrosis and regeneration with paucity or absence of inflammatory cells in muscle biopsy. Two autoantibodies, namely anti-signal recognition particle (SRP)-antibodies and anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-antibodies, are typically specific with NAM. Anti-SRP-positive NAM can be associated with cardiomyopathy which responds well to immunotherapy. Here we reported an anti-SRP-antibody and anti-MDA5-antibody NAM patient who developed severe cardiomyopathy after gaining significant improvement of myopathy and subsequently accepted heart transplantation. CASE PRESENTATION: A NAM case with both positive anti-SRP and MDA-5 antibodies who gained significant improvement of the skeletal muscle weakness with immunotherapy, but 3 years later he developed severe dilated cardiomyopathy and at last received heart transplantation. Myocardial biopsy showed disarranged and atrophic myofibers, remarkable interstitial fibrosis without inflammatory infiltrates. Immunohistochemistry analysis revealed increased polyubiquitin-binding protein p62/SQSTM1 protein expression and the positive staining of cleaved-caspase 3 in a few cardiomyocytes. After the transplantation, the patient was symptom-free on oral prednisone (10 mg/day) and tacrolimus (2 mg/day). CONCLUSIONS: We described the first case of anti-SRP and anti-MAD5 positive NAM who had received heart transplantation because of cardiopathy. Though the myopathy had been clinically improved after immunotherapy, the cardiomyopathy remained progressive and lethal. The processes of dysfunctional autophagy and augmented apoptosis were putatively pathophysiological mechanisms underlying cardiac damage in anti-SRP and anti-MAD5 positive NAM.

Enhanced cytokine expression and upregulation of inflammatory signaling pathways in broiler chickens affected by wooden breast myopathy.

BACKGROUND: Wooden breast (WB) myopathy in broiler chickens is a growing challenge for the poultry industry. Previous multi-omic data have implied that the pathogenesis of WB is associated with the activation of immune system and inflammatory response. However, the intricate mechanisms are not fully understood. This study was therefore conducted to systematically investigate the morphology, expression of cytokines as well as the underlying signaling pathways regulating the inflammatory response in pectoralis major (PM) muscle of WB myopathic broilers. RESULTS: wHistopathological changes, increased plasma creatine kinase and lactate dehydrogenase activities, elevated myeloperoxidase activity and overproduction of nitric oxide in muscle indicated the enhancement of muscle damage and inflammation in WB broilers. The messenger RNA (mRNA) expressions of inflammatory cytokines were dysregulated in PM muscle and contents of interleukin (IL)-1ß, IL-8 and tumor necrosis factor-α were increased in serum of WB myopathic broilers, indicating this myopathy was associated with immune disorder and systemic inflammation response. Additionally, toll-like receptor (TLR) levels were upregulated, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway was activated and the mRNA expression levels of downstream inflammatory mediators were enhanced in PM muscle of WB myopathy affected birds. CONCLUSION: The results indicated an immune disorder and a systemic inflammation response in WB myopathic broilers, which might be related to a synergetic effect of TLRs and NF-κB pathway. © 2020 Society of Chemical Industry.

Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation.

BACKGROUND: Necrotizing myopathy (NM) is defined by the dominant pathological feature of necrosis of muscle fibers without substantial lymphocytic inflammatory infiltration. Anti-signal recognition particle (SRP)-antibody-positive myopathy is related to NM. Anti-SRP-antibody-positive myopathy can comorbid with other disorders in some patients, however, comorbidity with malignant tumor and myopericarditis has still not been reported. CASE PRESENTATION: An 87-year-old woman with dyspnea on exertion and leg edema was referred to our hospital because of suspected heart failure and elevated serum creatine kinase level. Upon hospitalization, she developed muscle weakness predominantly in the proximal muscles. Muscle biopsy and immunological blood test led to the diagnosis of anti-SRP-antibody-positive myopathy. A colon carcinoma was also found and surgically removed. The muscle weakness remained despite the tumor resection and treatment with methylprednisolone. Cardiac screening revealed arrhythmia and diastolic dysfunction with pericardial effusion, which recovered with intravenous immunoglobulin (IVIg) treatment. CONCLUSIONS: We reported the first case of anti-SRP-positive myopathy comorbid with colon carcinoma and myopericarditis. This case is rare in the point that heart failure symptoms were the first clinical presentation. The underlying mechanism is still not clear, however, physicians should be carefully aware of the neoplasm and cardiac involvement in anti-SRP-antibody positive-myopathy patients and should consider farther evaluation and management.

Immunotherapy-refractory vacuolar myopathy with mucin deposition in scleromyxedema: A possible role of fibroblast growth factor 2.

Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-associated vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.

Real-time RT-qPCR assay to detect sequences in the Piscine orthoreovirus-1 genome segment S1 associated with heart and skeletal muscle inflammation in Atlantic salmon.

During the last decade, Piscine orthoreovirus was identified as the main causative agent of heart and skeletal muscle inflammation (HSMI) in Atlantic Salmon, Norway. A recent study showed that PRV-1 sequences from salmonid collected in North Atlantic Pacific Coast (NAPC) grouped separately from the Norwegian sequences found in Atlantic Salmon diagnosed with HSMI. Currently, the routine assay used to screen for PRV-1 in NAPC water and worldwide cannot differentiate between the two groups of PRV-1. Therefore, this study aimed at developing a real-time polymerase chain reaction (RT-qPCR) assay to target the PRV-1 genome segments specific for variants associated with HSMI. The assay was optimized and tested against 71 tissue samples collected from different regions including Norway, Chile and both coast of Canada and different hosts farmed Atlantic Salmon, wild Coho Salmon and escaped Atlantic Salmon collected in British Columbia, West Coast of Canada. This assay has the potential to be used for screening salmonids and non-salmonids that may carry PRV-1 potentially causing HSMI.

Expression of myxovirus-resistance protein A: a possible marker of muscle disease activity and autoantibody specificities in juvenile dermatomyositis.

AIMS: To evaluate the relationship between expression of myxovirus-resistance protein A (MxA) protein on muscle biopsies by immunohistochemistry and disease activity in juvenile dermatomyositis (JDM) patients. Also, another aim was to investigate whether the expression of MxA is related with myositis-specific autoantibodies (MSA) status in JDM patients. METHODS: 103 patients (median aged 6.3, interquartile range 0.5-15.9) enrolled in the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS). Muscle biopsies were stained with MxA and scored. Clinical data at initial presentation were collected and autoantibodies were analysed. Multiple linear regression analysis was performed to estimate the association between MxA expression on muscle fibres and muscle disease activity, and MSA status. RESULTS: Expression of MxA protein on JDM samples was identified in 61.2%. There was a significant association between MxA scores and Childhood Myositis Assessment Scale (CMAS) (P = 0.002), and Manual Muscle Testing of Eight Muscles (MMT8) (P = 0.026). CMAS and MMT8 scores were significantly lower in the group of patients with strong MxA expression. MxA scores differed according to MSA subgroups (P = 0.002). Patients with positive nuclear matrix protein 2 autoantibodies had strong MxA expression, whereas anti-melanoma differentiation-associated gene 5 positive patients had no or weak MxA expression. CONCLUSIONS: This study reveals the significant association between level of MxA expression on muscle fibres and clinical measures of muscular disease activity in JDM patients and MSA status. This confirms type I interferonopathies in muscle fibres of JDM patients which could help with improving treatment outcome in JDM patients and underscoring the distinct pathophysiological pathways in different MSA status.

A moderate oestradiol level enhances neutrophil number and activity in muscle after traumatic injury but strength recovery is accelerated.

KEY POINTS: The female hormone oestrogen may protect muscle from injury by reducing inflammation but this is debatable. In this study, the inflammatory response of injured muscle from oestrogen-replete mice was comprehensively compared to that from oestrogen-deficient mice. We show that oestrogen markedly promotes movement of neutrophils, an inflammatory white blood cell type, into muscle over the first few days after injury but has only a minor effect on the movement of macrophages, another inflammatory cell type. Despite the enhancement of inflammation by oestrogen in injured muscle, we found strength in oestrogen-replete mice to recover faster and to a greater extent than it does in oestrogen-deficient mice. Our study and others indicate that lower doses of oestrogen, such as that used in our study, may affect muscle inflammation and injury differently from higher doses. ABSTRACT: Oestrogen has been shown to protect against skeletal muscle injury and a reduced inflammatory response has been suggested as a possible protective mechanism. There are, however, dissenting reports. Our objective was to conduct an unbiased, comprehensive study of the effect of oestradiol on the inflammatory response following muscle injury. Female C57BL6/J mice were ovariectomized and supplemented with and without oestradiol. Tibialis anterior muscles were freeze injured and studied primarily at 1-4 days post-injury. Oestradiol supplementation increased injured muscle gene expression of neutrophil chemoattractants (Cxcl1 and Cxcl5) and to a lesser extent that of monocyte/macrophage chemoattractants (Ccl2 and Spp1). Oestradiol markedly increased gene expression of the neutrophil cell surface marker (Ly6g) but had less consistent effects on the monocyte/macrophage cell surface markers (Cd68, Cd163 and Cd206). These results were confirmed at the protein level by immunoblot with oestradiol increasing LY6G/C content and having no significant effect on CD163 content. These findings were confirmed with fluorescence-activated cell sorting counts of neutrophils and macrophages in injured muscles; oestradiol increased the proportion of CD45+ cells that were neutrophils (LY6G+ ) but not the proportion that were macrophages (CD68+ or CD206+ ). Physiological impact of the oestradiol-enhanced neutrophil response was assessed by strength measurements. There was no significant difference in strength between oestradiol-supplemented and -unsupplemented mice until 2 weeks post-injury; strength was 13-24% greater in supplemented mice at 2-6 weeks post-injury. In conclusion, a moderate level of oestradiol supplementation enhances neutrophil infiltration in injured muscle and this is associated with a beneficial effect on strength recovery.

Toxic myopathies.

PURPOSE OF REVIEW: Our aim is to highlight major advances reported in the last few years in drug-induced muscle toxicity. RECENT FINDINGS: Our focus is on myopathies induced by statins and immune checkpoint inhibitors with a brief overview of rare steroid myopathies. Statin muscle injury is frequently because of direct toxicity rather than an autoimmune mechanism. Laboratory testing and muscle pathologic features distinguish these two conditions. Statin-associated necrotizing autoimmune myopathy (SANAM) is associated with an autoantibody in 66% of cases targeting the HMGCR enzyme. The later autoantibody is a marker for necrotizing autoimmune myopathy, regardless of statin exposure. In SANAM, MHC-I antigens are expressed on the surface of intact muscle fibers. Genetic HLA loci predispose patients exposed to statins to immunologic toxicity. SANAM requires long-term therapy with multiple immunosuppressive therapies. Immune checkpoint inhibitors are powerful emerging therapies for advanced cancer that pause a novel therapeutic challenge. SUMMARY: This review is focused on statins, the most prevalent myotoxic drug class. In addition, we examine the accumulating body of evidence of muscle injury and its management with immune checkpoint inhibitors. We anticipate the reader to become more knowledgeable in recent discoveries related to these myotoxic drugs, and their mechanisms of action and management.

Pathogenic role of anti-signal recognition protein and anti-3-Hydroxy-3-methylglutaryl-CoA reductase antibodies in necrotizing myopathies: Myofiber atrophy and impairment of muscle regeneration in necrotizing autoimmune myopathies.

OBJECTIVE: Immune-mediated necrotizing myopathies (IMNM) may be associated with either anti-signal recognition protein (SRP) or anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibodies (Abs), and the titer of these Abs is correlated with disease activity. We investigated whether anti-SRP and anti-HMGCR Abs could be involved in muscle damage. METHODS: Muscle biopsies of patients were analyzed for atrophy and regeneration by measuring fiber size and by performing immunostaining of neonatal myosin heavy chain. To further understand the role of the Abs in the pathology, we performed muscle cell coculture with the Abs. Atrophy and regeneration were evaluated based on the myotube surface area as well as gene and cytokine profiles. RESULTS: In muscle biopsies of patients with anti-SRP+ and anti-HMGCR+ Abs, a large number of small fibers corresponding to both atrophic and regenerating fibers were observed. In vitro, anti-SRP and anti-HMGCR Abs induced muscle fiber atrophy and increased the transcription of MAFbx and TRIM63. In addition, the muscle fiber atrophy was associated with high levels of inflammatory cytokines: tumor necrosis factor, interleukin (IL)-6, and reactive oxygen species. In the presence of anti-SRP or anti-HMGCR Abs, mechanisms involved in muscle regeneration were also impaired due to a defect of myoblast fusion. This defect was associated with a decreased production of IL-4 and IL-13. The addition of IL-4 and/or IL-13 totally rescued fusion capacity. INTERPRETATION: These data show that molecular mechanisms of atrophy and regeneration are affected and contribute to loss of muscle function occurring in IMNM. This emphasizes the potential interest of targeted therapies addressing these mechanisms. Ann Neurol 2017;81:538-548.

Statin-associated immune-mediated necrotising myopathy: a New Zealand case series showing possible overrepresentation in Pacific Islanders.

BACKGROUND: Statin-associated immmune-mediated necrotising myopathy (IMNM) is an emerging entity. Being an uncommon condition, our knowledge and understanding is largely based on case series. AIM: To review incident cases of statin-associated IMNM associated with anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibodies in a single New Zealand centre over a 2-year period. METHODS: Four incident cases of statin-associated IMNM were seen between 2014 and 2016. Their presentation, investigation, treatment and current response to treatment are summarised. Two of the four patients were Pacific Islanders despite a small Pacific Island population in the southern district health board. A literature search was performed focusing on the presentation, investigation and treatment of statin-associated IMNM and also genetic associations with this entity to determine whether Pacific Islanders may be at increased risk RESULTS: All four patients presented with profound weakness and recent exposure to atorvastatin. All proceeded to muscle biopsy. Two biopsies showed typical IMNM. One biopsy had mild changes, reported as possibly being compatible with anti-HMGCR antibodies. The final biopsy had features consistent with IMNM, with some features suggestive of polymyositis. Two recent studies have shown an association between anti-HMGCR antibodies and the HLA-DRB1*11:01 haplotype. Interestingly, HLA-DRB1 alleles (including HLA-DRB1*11:01) were observed to be among the most frequent alleles in a Pacific Island population study. CONCLUSION: This is the first case series of statin-associated IMNM with a focus on Pacific Islanders and raises the possibility that Pacific Islanders exposed to statins may be at increased risk of developing an immune-mediated myopathy.