Neuromuscular complications of the lower extremity after thrombectomy in a patient with superficial femoral artery occlusion: Case series.

BACKGROUND: Ischemia reperfusion (IR) injury may result in rhabdomyolysis and compartment syndrome when blood supply returns after thrombectomy for patients with acute limb ischemia. OBJECTIVE: We highlight the value of early diagnosis and treatment in post-thrombectomy patients with IR injuries in their lower legs. CASE DESCRIPTION: Two patients received thrombectomy due to left superficial femoral artery occlusion. Both patients complained of left calf pain during ambulation at the 1- and 3-day follow up post-thrombectomy, as well as a heating sensation, swelling, weakness, and sensory changes in the affected leg. For early diagnosis musculoskeletal ultrasounds were performed and in both cases revealed swelling and change of echogenicity in the left calf. To further diagnosis, magnetic resonance imaging of the left leg revealed limb IR-induced muscular injury and rhabdomyolysis, respectively. In both cases, an electrodiagnostic study revealed peripheral nerve injury in the left leg. Medications were provided for neuropathic pain control and early rehabilitation was performed to improve function. In both cases, patients reported during their follow-up that their pain and muscle weakness had improved. CONCLUSION: When post-thrombectomy calf pain occurs early evaluation and treatment should be performed to identify any potential IR injury.

Modulation of inflammatory, oxidative, and apoptotic stresses mediates the renoprotective effect of daidzein against glycerol-induced acute kidney injury in rats.

Acute kidney injury (AKI) is a life-threatening complication that accompanies rhabdomyolysis. Daidzein is a dietary isoflavone that has various biological activities. This study examined the therapeutic potential of daidzein and the underlying mechanisms against AKI induced by glycerol in male rats. Animals were injected once with glycerol (50%, 10 ml/kg, intramuscular) for induction of AKI and pre-treated orally with daidzein (25, 50, and 100 mg/kg) for 2 weeks. Biochemical, histopathological, immunohistopathological, and molecular parameters were assessed to evaluate the effect of daidzein. The results revealed that the model group displayed remarkable functional, molecular, and structural changes in the kidney. However, pre-administration of daidzein markedly decreased the kidney relative weight as well as the levels of urea, creatinine, K, P, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C. Further, daidzein lessened the rhabdomyolysis-related markers [lactate dehydrogenase (LDH) and creatine kinase (CK)]. Notably, the enhancement of the antioxidant biomarkers [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and reduced glutathione (GSH) is accompanied by a decrease in malondialdehyde (MDA) and nitric oxide (NO) levels. Moreover, upregulated gene expression levels of nuclear factor erythroid 2-related factor 2 (Nfe212) and hemeoxygenase-1 (Hmox1) were exerted by daidzein administration. Rats who received daidzein displayed markedly lower interleukin-1ß (IL-1ß), tumor nuclear factor-α (TNF-α), myleoperoxidase (MPO), and nuclear factor kappa B (NF-κB) levels together with higher interleukin-10 (IL-10) related to the model group. Remarkably, significant declines were noticed in the pro-apoptotic (Bax and caspase-3) and rises in antiapoptotic (Bcl-2) levels in the group that received daidzein. The renal histological screening validated the aforementioned biochemical and molecular alterations. Our findings support daidzein as a potential therapeutic approach against AKI-induced renal injury via suppression of muscle degradation, oxidative damage, cytokine release, and apoptosis.

In vivo dynamics of senescence in rhabdomyolysis-induced acute kidney injury.

Cellular senescence is involved in the pathogenesis of various diseases, including acute kidney injury (AKI). AKI is defined as a sudden loss of kidney function. In severe AKI, irreversible loss of kidney cells can occur. Cellular senescence might contribute to this maladaptive tubular repair, though, its pathophysiological role in vivo is incompletely understood. In this study, we used p16-CreERT2-tdTomato mice in which cells with high p16 expression, a prototypical senescent marker, are labeled with tdTomato fluorescence. Then, we induced AKI by rhabdomyolysis and traced the cells with high p16 expression following AKI. We proved that the induction of senescence was observed predominantly in proximal tubular epithelial cells (PTECs) and occurred in a relatively acute phase within 1-3 days after AKI. These acute senescent PTECs were spontaneously eliminated by day 15. On the contrary, the generation of senescence in PTECs persisted during the chronic recovery phase. We also confirmed that the kidney function did not fully recover on day 15. These results suggest that the chronic generation of senescent PTECs might contribute to maladaptive recovery from AKI and lead to chronic kidney disease progression.

A Novel Rabbit Anti-Myoglobin Monoclonal Antibody's Potential Application in Rhabdomyolysis Associated Acute Kidney Injury.

Myoglobin (Mb) is the main constituent of vertebrate skeletal muscle and myocardium and plays an essential role in oxygen binding, storage, transport, and earliest disease diagnosis. This study focuses on preparing the novel recombinant rabbit anti-Mb monoclonal antibody and applying it to a diagnosis of Mb deposition in rhabdomyolysis-associated acute kidney injury (RM-AKI). The full-length coding sequence of rat Mb was cloned and expressed, and the high-quality and titer rabbit anti-Mb polyclonal antibodies were produced by the immunogen His-Mb fusion protein. A new hybridoma cell was obtained by hybridoma screening technology. With the help of DNA sequencing and a molecular clonal, anti-Mb monoclonal antibody heavy and light chains expression plasmid was constructed. Finally, the recombinant rabbit anti-Mb monoclonal antibody with extraordinarily high affinity (KD = 1.21 pM) was obtained. Meanwhile, it had broad species reactivity (mouse, rat, human, and horse) and good tissue specificity (skeletal muscle and myocardium). It also had a very good performance in western blotting, immunohistochemistry, and immunofluorescence assay to detect the Mb level in the kidney, myocardium, and skeletal muscle of RM-AKI. This study will be significantly helpful for Mb-associated disease diagnosis, and pathogenesis exploration, and further may act as a neutralizing antibody for disease treatment.

Ultrasmall and highly biocompatible carbon dots derived from natural plant with amelioration against acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) refers to a tricky clinical disease, known by its high morbidity and mortality, with no real specific medicine for AKI. The carbonization product from Pollen Typhae (i.e., Pu-huang in China) has been extensively employed in clinic, and it is capable of relieving the renal damage and other diseases in China since acient times. RESULTS: Inspired by the carbonization process of Traditional Chinese Medicine (TCM), a novel species of carbon dots derived from Pollen Typhae (PT-CDs) was separated and then collected using a one-pot pyrolysis method. The as-prepared PT-CDs (4.85 ± 2.06 nm) with negative charge and abundant oxygenated groups exhibited high solubility, and they were stable in water. Moreover, the rhabdomyolysis (RM)-induced AKI rat model was used, and it was first demonstrated that PT-CDs had significant activity in improving the level of BUN and CRE, urine volume and kidney index, and histopathological morphology in RM-induced AKI rats. It is noteworthy that interventions of PT-CDs significantly reduced degree of inflammatory reaction and oxidative stress, which may be correlated with the basial potential mechanism of anti-AKI activities. Furthermore, cytotoxicity assay and biosafety evaluation exhibited high biocompatibility of PT-CDs. CONCLUSION: This study offers a novel relieving strategy for AKI based on PT-CDs and suggests its potential to be a related candidate for clinical applications.

Myoglobin cast nephropathy following multiple bee stings.

Bee stings usually result in mild allergic reactions; however, mass envenomation can cause severe complications such as rhabdomyolysis, hemolysis, shock, or multi-organ damage. Rhabdomyolysis can result in acute renal failure either by tubular obstruction by myoglobin casts or by direct cytotoxic injury. We present a case of a 12-year-old female child who presented with sudden onset anuria and hypertension following mass envenomation by bees. A renal biopsy was performed, the microscopic evaluation of which revealed tubular injury, with associated intratubular pigmented casts. The casts stained positive for myoglobin immunohistochemical stain, thus confirming a diagnosis of myoglobin cast nephropathy. The patient was given IV steroids and underwent seven sessions of hemodialysis, following which there was complete recovery of renal function.

A young female case of asymptomatic immune-mediated necrotizing myopathy: a potential diagnostic option of antibody testing for rhabdomyolysis.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) is a neuromuscular disorder that presents muscle weakness in proximal extremities and/or the trunk with an elevation of creatine kinase (CK). Young and asymptomatic anti-HMGCR IMNM patients are very rare and a treatment regimen has not been established. The present case, a 17-year-old woman without any muscular symptoms, only showed hyperCKemia that was detected by chance. After close examinations, including a muscle biopsy and antibody search, she was diagnosed as anti-HMGCR IMNM, and initial treatment with methotrexate and continuous intravenous immunoglobulin seemed to be effective. The present case is the unusually young asymptomatic case of anti-HMGCR IMNM. The diagnosis was successfully made, leading to the early introduction of a treatment. Given the course of this case, we believe that the preceding antibody testing is one of the diagnostic option for rhabdomyolysis.

Blocking Periostin Prevented Development of Inflammation in Rhabdomyolysis-Induced Acute Kidney Injury Mice Model.

BACKGROUND: Rhabdomyolysis is the collapse of damaged skeletal muscle and the leakage of muscle-cell contents, such as electrolytes, myoglobin, and other sarcoplasmic proteins, into the circulation. The glomeruli filtered these products, leading to acute kidney injury (AKI) through several mechanisms, such as intratubular obstruction secondary to protein precipitation. The prognosis is highly mutable and depends on the underlying complications and etiologies. New therapeutic plans to reduce AKI are now needed. Up to now, several cellular pathways, with the nuclear factor kappa beta (NF-kB), as well as the proinflammatory effects on epithelial and tubular epithelial cells, have been recognized as the major pathway for the initiation of the matrix-producing cells in AKI. Recently, it has been mentioned that periostin (POSTN), an extracellular matrix protein, is involved in the development of inflammation through the modulation of the NF-kB pathway. However, how POSTN develops the inflammation protection in AKI by rhabdomyolysis is uncertain. This study aimed to investigate the role of POSTN in a rhabdomyolysis mice model of AKI induced by an intramuscular injection of 50% glycerol. METHODS: In vivo, we performed an intramuscular injection of 50% glycerol (5 mg/kg body weight) to make rhabdomyolysis-induced AKI. We examined the expression level of POSTN through the progression of AKI after glycerol intramuscular injection for C57BL/6J wildtype (WT) mice. We sacrificed mice at 72 h after glycerol injection. We made periostin-null mice to examine the role of POSTN in acute renal failure. The role of periostin was further examined through in vitro methods. The development of renal inflammation is linked with the NF-kB pathway. To examine the POSTN function, we administrated hemin (100 µM) on NIH-3T3 fibroblast cells, and the following signaling pathways were examined. RESULTS: The expression of periostin was highly increased, peaking at about 72 h after glycerol injection. The expression of inflammation-associated mRNAs such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-a) and IL-6, and tubular injury score in H-E staining were more reduced in POSTN-null mice than WT mice at 72 h after glycerol injection. CONCLUSION: POSTN was highly expressed in the kidney through rhabdomyolysis and was a positive regulator of AKI. Targeting POSTN might propose a new therapeutic strategy against the development of acute renal failure.

ACSL4 contributes to ferroptosis-mediated rhabdomyolysis in exertional heat stroke.

BACKGROUND: Rhabdomyolysis (RM) is a common complication of exertional heat stroke (EHS) and constitutes a direct cause of death. However, the mechanism underlying RM following EHS remains unclear. METHODS: The murine EHS model was prepared by our previous protocol. RNA sequencing is applied to identify the pathological pathways that contribute to RM following EHS. Inhibition of the acyl-CoA synthetase long-chain family member 4 (ACSL4) was achieved by RNA silencing in vitro prior to ionomycin plus heat stress exposure or pharmacological inhibitors in vivo prior to heat and exertion exposure. The histological changes, the iron accumulation, oxidized phosphatidylethanolamines species, as well as histological evaluation and levels of lipid metabolites in skeletal muscle tissues were measured. RESULTS: We demonstrated that ferroptosis contributes to RM development following EHS. Ferroptosis inhibitor ferrostatin-1 administration once EHS onset significantly ameliorated the survival rate of EHS mice from 35.357% to 52.288% within 24 h after EHS (P = 0.0028 compared with control) and markedly inhibited RM development induced by EHS. By comparing gene expression of between sham heat rest (SHR) (n = 3) and EHS (n = 3) mice in the gastrocnemius (Gas) muscle tissue, we identified that Acsl4 mRNA expression is elevated in Gas muscle tissue of EHS mice (P = 0.0038 compared with SHR), so as to its protein levels (P = 0.0001 compared with SHR). Followed by increase in creatine kinase (CK) and myoglobin (MB) levels, the labile iron accumulation, decrease in glutathione peroxidase 4 (GPX4) expression, and elevation of lipid peroxidation products. From in vivo and in vitro experiments, inhibition of Acsl4 significantly improves muscle cell death caused by EHS, thereby ameliorating RM development, followed by reduction in CK and MB levels by 30-40% (P < 0.0001; n = 8-10) and 40% (P < 0.0001; n = 8-10), restoration of GPX4 expression, and decrease in lipid peroxidation products. Mechanistically, ACSL4-mediated RM seems to be Yes-associated protein (YAP) dependent via TEA domain transcription factor1/TEA domain transcription factor4. CONCLUSIONS: These findings demonstrate an important role of ACSL4 in mediating ferroptosis activation in the development of RM following EHS and suggest that targeting ACSL4 may represent a novel therapeutic strategy to limit the skeletal muscle cell death and prevent RM after EHS.

Bi-allelic loss-of-function OBSCN variants predispose individuals to severe recurrent rhabdomyolysis.

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, most cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified 10 bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) predisposing individuals to recurrent rhabdomyolysis. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in sarcoplasmic reticulum function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in sarcoplasmic reticulum Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the sarcoplasmic reticulum and/or a decrease in Ca2+ sarcoplasmic reticulum storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.

Case Report: ANCA-Associated Vasculitis Presenting With Rhabdomyolysis and Pauci-Immune Crescentic Glomerulonephritis After Pfizer-BioNTech COVID-19 mRNA Vaccination.

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for COVID-19 vaccines to control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge with regard to adverse events of COVID-19 vaccines during post-marketing surveillance. Interestingly, four cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) presenting with pauci-immune crescentic glomerulonephritis (GN) after COVID-19 mRNA vaccination have already been reported. We here expand our current knowledge of this rare but important association and report a case of AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN after Pfizer-BioNTech COVID-19 mRNA vaccination. As huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must continue to assess vaccine safety important for the detection of any events associated with COVID-19 vaccination. This is especially relevant in complex diseases where diagnosis is often challenging, as in our patient with AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN.

Compromised mitochondrial quality control triggers lipin1-related rhabdomyolysis.

LPIN1 mutations are responsible for inherited recurrent rhabdomyolysis, a life-threatening condition with no efficient therapeutic intervention. Here, we conduct a bedside-to-bench-and-back investigation to study the pathophysiology of lipin1 deficiency. We find that lipin1-deficient myoblasts exhibit a reduction in phosphatidylinositol-3-phosphate close to autophagosomes and late endosomes that prevents the recruitment of the GTPase Armus, locks Rab7 in the active state, inhibits vesicle clearance by fusion with lysosomes, and alters their positioning and function. Oxidized mitochondrial DNA accumulates in late endosomes, where it activates Toll-like receptor 9 (TLR9) and triggers inflammatory signaling and caspase-dependent myolysis. Hydroxychloroquine blocks TLR9 activation by mitochondrial DNA in vitro and may attenuate flares of rhabdomyolysis in 6 patients treated. We suggest a critical role for defective clearance of oxidized mitochondrial DNA that activates TLR9-restricted inflammation in lipin1-related rhabdomyolysis. Interventions blocking TLR9 activation or inflammation can improve patient care in vivo.

Heme Burden and Ensuing Mechanisms That Protect the Kidney: Insights from Bench and Bedside.

With iron at its core, the tetrapyrrole heme ring is a cardinal prosthetic group made up of many proteins that participate in a wide array of cellular functions and metabolism. Once released, due to its pro-oxidant properties, free heme in sufficient amounts can result in injurious effects to the kidney and other organs. Heme oxygenase-1 (HO-1) has evolved to promptly attend to such injurious potential by facilitating degradation of heme into equimolar amounts of carbon monoxide, iron, and biliverdin. HO-1 induction is a beneficial response to tissue injury in diverse animal models of diseases, including those that affect the kidney. These protective attributes are mainly due to: (i) prompt degradation of heme leading to restraining potential hazardous effects of free heme, and (ii) generation of byproducts that along with induction of ferritin have proven beneficial in a number of pathological conditions. This review will focus on describing clinical aspects of some of the conditions with the unifying end-result of increased heme burden and will discuss the molecular mechanisms that ensue to protect the kidneys.

Successful orthotopic heart transplantation in CPTII deficiency.

Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.

Rhabdomyolysis with myoglobin-induced acute kidney injury: A case series of four cases.

Rhabdomyolysis is a potentially life-threatening clinical syndrome characterized by the breakdown of skeletal muscle cells and release of creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin into the plasma and interstitial space. Rhabdomyolysis can occur due to a variety of causes and acute kidney injury (AKI) is one of its most dreaded complications occurring in 33%-50% patients. The main pathophysiology of renal injury is due to vasoconstriction, intraluminal casts, tubular obstruction, and direct myoglobin toxicity. As the symptoms are nonspecific, a high level of suspicion is required in the mind of the treating physician. Early diagnosis and prompt management with fluid resuscitation, initiation of renal replacement therapy (RRT), and elimination of causative agents can help prevent complications. We hereby report four interesting cases of this clinical syndrome with emphasis on the causative agents.

MTP deficiency caused by HADHB mutations: Pathophysiology and clinical manifestations.

Mutations in the HADHB gene lead to Mitochondrial Trifunctional Protein (MTP) deficiency. MTP deficiency is a rare autosomal recessive disorder affecting long-chain fatty acid oxidation. Patients affected by MTP deficiency are unable to metabolize long-chain fatty-acids and suffer a variety of symptoms exacerbated during fasting. The three phenotypes associated with complete MTP deficiency are an early-onset cardiomyopathy and early death, an intermediate form with recurrent hypoketotic hypoglycemia and a sensorimotor neuropathy with episodic rhabdomyolysis with small amount of residual enzyme activities. This review aims to discuss the pathophysiological mechanisms and clinical manifestations of each phenotype, which appears different and linked to HADHB expression levels. Notably, the pathophysiology of the sensorimotor neuropathy is relatively unknown and we provide a hypothesis on the qualitative aspect of the role of acylcarnitine buildup in Schwann cells in MTP deficiency patients. We propose that acylcarnitine may exit the Schwann cell and alter membrane properties of nearby axons leading to axonal degeneration based on recent findings in different metabolic disorders.

MYH1 is a candidate gene for recurrent rhabdomyolysis in humans.

Rhabdomyolysis is a serious medical condition characterized by muscle injury, and there are recognized genetic causes especially in recurrent forms. The majority of these cases, however, remain unexplained. Here, we describe a patient with recurrent rhabdomyolysis in whom extensive clinical testing failed to identify a likely etiology. Whole-exome sequencing revealed a novel missense variant in MYH1, which encodes a major adult muscle fiber protein. Structural biology analysis revealed that the mutated residue is extremely well conserved and is located in the actin binding cleft. Furthermore, immediately adjacent mutations in that cleft in other myosins are pathogenic in humans. Our results are consistent with the finding that MYH1 is mutated in rhabdomyolysis in horses and suggest that this gene should be investigated in cases with recurrent rhabdomyolysis.

The spectrum of peripheral neuropathy in disorders of the mitochondrial trifunctional protein.

Peripheral neuropathy is a known irreversible long-term complication of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), two inherited disorders of mitochondrial long-chain fatty acid oxidation. The underlying pathophysiology of neuropathy is still not fully understood. We report electrophysiological studies and neurological findings in a series of 8 LCHAD-deficient and 11 MTP-deficient patients. The median age at time of the study was 8.0 years (0.5-25 years). The overall prevalence of neuropathy was 58% with neuropathic symptoms being slightly more common in MTPD compared to LCHADD (70% vs 50%, respectively). Onset of neuropathy was significantly earlier in MTPD patients compared to LCHADD patients (median age at onset 4.7 vs 15.3 years, respectively, P = .047). In four patients, isolated peripheral neuropathy was the first and only presenting symptom, and in all four the diagnosis was missed by newborn screening. About half of the patients (45.5%) had a sensorimotor neuropathy, while 27.3% showed a pure motor form and another 27.3% an isolated sensory form. Despite early diagnosis by newborn screening and early initiation of therapy, peripheral neuropathy cannot be prevented in all patients with LCHADD/MTPD and has severe impact on the life of affected patients. Electrophysiology classifies LCHADD/MTPD neuropathy as axonal with secondary demyelination. A novel observation is that in patients with acute, fulminant onset of neuropathy, symptoms can be partly reversible. Further studies are needed to elucidate the underlying pathophysiology of axonal damage and possible therapeutic targets.

Genetic inhibition of FABP4 attenuated endoplasmic reticulum stress and mitochondrial dysfunction in rhabdomyolysis-induced acute kidney injury.

AIMS: Rhabdomyolysis-associated acute kidney injury (AKI) is life-threatening but effective treatments is lacking. Recently, fatty acid-binding protein 4 (FABP4) has been identified as a mediator of ischemic and toxic AKI through regulating endoplasmic reticulum (ER) stress in our previous studies. However, the role of FABP4 in rhabdomyolysis-induced AKI and extended organelle dysfunctions need to be explored and validated. MAIN METHODS: We firstly performed mRNA-seq and bioinformatic analysis to investigate the role of FABP4. The mouse model was established via injecting glycerol to FABP4 wild type (WT) and knockout (KO) mice. Blood biochemical, inflammatory and apoptotic parameters were measured and compared across groups. Representative pathways of ER stress and mitochondrial dysfunction were also detected and quantified. KEY FINDINGS: Comparing FABP4 WT and FABP4 KO model groups, FABP4 deficiency significantly attenuated renal dysfunction, by reducing serum creatinine (165.90 ± 15.61 µmol/L vs 35.5 ± 8.33 µmol/L, p < 0.0001) and blood urea nitrogen (89.78 ± 6.82 mmol/L vs 19.75 ± 5.97 mmol/L, p < 0.0001), and alleviating tubular injury scores. Inflammatory and apoptotic responses were alleviated by FABP4 genetic inhibition. Mechanistically, glycerol injection triggered ER stress characterized by activated IRE1, PERK, and ATF6 signaling pathways, and induced mitochondrial dysfunction supported by ultrastructural damage, energy metabolic derangement, and excessive mitochondrial fission (upregulated DRP1/downregulated OPA1). These two organelle dysfunctions were effectively relieved by FABP4 deficiency. SIGNIFICANCE: Taken together, genetic inhibition of FABP4 protected against rhabdomyolysis-induced AKI via reducing ER stress as well as mitochondrial dysfunction. FABP4 might act as a novel therapeutic target in rhabdomyolysis-induced AKI.

A rare case of adult herpes simplex encephalitis complicated with rhabdomyolysis.

BACKGROUND: Compelling evidence indicates that status epilepticus is a prevalent cause of rhabdomyolysis. However, cases of rhabdomyolysis induced by a single seizure accompanied by viral encephalitis are rarely reported. Herein, we present a case of adult Herpes Simplex Encephalitis complicated with rhabdomyolysis. CASE PRESENTATION: A 32-year-old male was patient presented with fever accompanied by episodes of convulsions, myalgia, and oliguria, which exacerbated the delirium. Routine blood examination showed impaired kidney function and elevated myoglobin (Mb) and creatine phosphokinase (CK) levels. MRI scanning revealed a damaged frontotemporal lobe and limbic system. In addition, herpes simplex virus (HSV) pathogen was identified in the cerebrospinal fluid thus indicating HSV infection. Therefore, a diagnosis of rhabdomyolysis triggered by HSV infection accompanied by epilepsy was made. Notably, the patient recovered well after early intervention and treatment. CONCLUSION: The case presented here calls for careful analysis of rhabdomyolysis cases with unknown causes, minor seizures, and without status epilepticus. This case also indicates that HSV virus infection might contribute to the rhabdomyolysis.