Table 1 Iron metabolism and ferroptosis in muscle diseases and disorders

Skeletal muscle diseases and disorders

Age related-sarcopenia

Iron overload was detected in the atrophic muscles of sarcopenia animal models and patients.^73,291,292 The expressions of TfR1 decreased and SLC39A14 increased^23,289

The expression of SLC7A11 was decreased, GSH content was decreased, ROS accumulation and oxidative stress were increased.^73,524

Adipogenesis‐related genes such as Fasn and Adipoq were significantly induced, and activation of unsaturated fatty acid biosynthesis and lipid peroxidation increased.²³

Amyotrophic lateral sclerosis (ALS)

TfR1 and free iron levels were increased,⁵²⁵ and the expression of serum ferritin in ALS patients increased.⁵²⁶

Hypochlorous acid and its catalytic enzyme MPO increased, and GPX4 expression decreased.^302,303

C11-BODIPY fluorescence staining showed increased lipid peroxidation.⁵²⁵

Duchenne muscular dystrophy (DMD)

The level of total elemental iron and expression of ferritin and ferroportin increased in muscle.³⁰⁶

ROS accumulation and oxidative stress increased.³⁰⁶

The production of iron-dependent hydroxyl radicals and lipid peroxidation increased.³⁰⁷

Statin-induced rhabdomyolysis

Atorvastatin increased intracellular iron concentration in cardiomyocytes and muscle satellite cells in a dose-dependent manner.⁵²⁷

The cellular and mitochondrial ROS levels of cardiomyocytes and muscle stem cells were significantly increased after atorvastatin treatment.⁵²⁷

The expression of proteins related to lipid peroxidation, such as PTGS2/COX-2 and 4-HNE, and MDA levels were increased in cardiomyocytes and muscle stem cells after atorvastatin treatment.⁵²⁷

Glycerol-induced rhabdomyolysis

The expression of ferritin increased.⁵²⁸

The level of GSH decreased and the expression of heme oxygenase-1 (HO-1) increased.⁵²⁸

The contents of MDA and 4-HNE (lipid peroxidation products) increased.⁵²⁸

Exertional heat stroke (EHS)-induced rhabdomyolysis

Non-heme iron accumulated in muscle tissue. The expression of iron homeostasis related genes in gastrocnemius muscle was dysregulated, such as increased expression of TfR1, NCOA4, SLC39A14, and decreased expression of FTH1.³⁸

The expression of GPX4 in gastrocnemius muscle of mice in EHS model group was significantly decreased.³⁸

Increased lipid peroxidation, indicated by BODIPY 581/591 fluorescence and the increased lipid metabolites levels of MDA, 5‐HETE, and 15‐HETE were observed in muscle tissue after EHS.³⁸ The expressions of ACSL4 and PTGS2 were also significantly increased.³⁸

Malignancy tumor-induced muscular atrophy

The metal ion transporter SLC39A14 was found to be significantly upregulated in cachectic muscles.^309,312 The iron content and ferritin expression in muscle increased.³¹⁰

ROS, NOX2 and 3-NT levels were significantly elevated.³¹²

The levels of ACSL4, HO-1, and 4-HNE were significantly increased.³¹²

Myocardial diseases and disorders

Anthracycline-induced cardiomyopathy

HO-1 was significantly upregulated in the hearts of DOX-treated mice and non-heme iron was rapidly and systematically accumulated.³⁶

Cellular and mitochondrial ROS levels were increased.³²⁷ GPX4 expression was decreased, mitochondrial glutathione transporter SLC25A11 was down-regulated, and mitochondrial GSH level was decreased.⁵²⁹

The expression of PTGS2 and the levels of MDA and lipid ROS increased.⁵³⁰

Myocardial ischemia/reperfusion injury

The expression of TfR1 and NCOA4 were increased, FTH expression was decreased, and Fe²⁺ was deposited in myocardial tissue.^213,473

The ROS content of myocardial tissue increased³³⁶ and the activity of superoxide dismutase (SOD) and expressions of SLC7A11 and GPX4 decreased.⁴⁷²

The levels of ACSL4 and MDA increased.³³⁶

Diabetic cardiomyopathy

The level of ferritin in myocardial tissue was reduced.^123,185 Total iron and Fe²⁺ deposits were observed in myocardial tissue and cells.⁵³¹

GPX4 and SLC7A11 levels were reduced in myocardial tissue.¹⁸⁵ Oxidative stress increased in an AMPK-dependent manner and excess ROS production.³⁴⁶

The levels of PTGS2,¹²³ ACSL4,⁵³² MDA⁵³¹ and 4-HNE¹⁸⁵ were increased.