Growth differentiation factor 15 (GDF-15) is a stress-induced transforming growth factor-β superfamily cytokine with versatile functions in human health. Elevated GDF-15 blood levels associate with ...multiple pathological conditions, and are currently extensively explored for diagnosis, and as a means to monitor disease progression and evaluate therapeutic responses. This review analyzes GDF-15 in human conditions specifically focusing on its association with muscle manifestations of sarcopenia, mitochondrial myopathy, and autoimmune and viral myositis. The use of GDF-15 as a widely applicable health biomarker to monitor muscle disease is discussed, and its potential as a therapeutic target is explored.
Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis. This review ...explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in muscular dystrophies, disorders characterized by successive bouts of muscle fiber degeneration and regeneration in an attempt to repair contraction-induced damage. TLRs are defense receptors that detect infection and recognize self-molecules released from damaged cells. In muscular dystrophies, these receptors become over-active, and are firmly involved in the sustained chronic inflammation exhibited by the muscle tissue, via their induction of pro-inflammatory cytokine expression. Taming the exaggerated activation of TLR2/4 and TLR7/8/9, and their downstream effectors in particular, comes forward as a therapeutic strategy with potential to slow down disease progression.
In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake ...counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.
The cellular transcriptome contains a wide diversity of untranslated RNAs, of which the class of regulatory long noncoding RNAs (lncRNAs) has only recently been recognized. Evidence swiftly ...accumulates of lncRNAs influencing mitochondrial activities of eukaryotic cells, and perturbed expression is conspicuously associated with human diseases. In this review, we describe the multifaceted effects of lncRNAs on mitochondrial function, more particularly on the balance between oxidative phosphorylation and glycolysis, on the production of reactive oxygen species, and on apoptosis in human cells. Emphasis is placed on the involvement of lncRNAs in cancer metabolism, as tumor cells rely heavily on modifications of mitochondrial functioning as an essential component for sustained tumorigenesis and cancer progression. From the nonexhaustive list of lncRNAS described in this review, ANRIL, AScmtRNA, H19, HOTAIR, LincRNA-p21, MALAT1, RMRP, SAMMSON, and VL30 have emerged as potent regulators of mitochondrial metabolism. Due to their key role in cancer progression, they represent potential targets of innovative lncRNA-based treatment strategies.
The idiopathic inflammatory myopathies (IIM) constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (IBM) and ...necrotizing autoimmune myopathy (NAM). They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF), Interferons (IFNα/β/γ), Interleukins (IL-1/6/12/15/18/23) and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21). Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction.
Duchenne muscular dystrophy (DMD), the severest form of muscular dystrophy, is characterized by progressive muscle weakness with fatal outcomes most often before the fourth decade of life. Despite ...the recent addition of molecular treatments, DMD remains a disease without a cure, and the need persists for the development of supportive therapies aiming to help improve patients' quality of life. This review focuses on the therapeutical potential of amino acid and derivative supplements, summarizing results obtained in preclinical studies in murine disease models. Several promising compounds have emerged, with L-arginine, N-acetylcysteine, and taurine featuring among the most intensively investigated. Their beneficial effects include reduced inflammatory, oxidative, fibrotic, and necrotic damage to skeletal muscle tissues. Improvement of muscle strength and endurance have been reported; however, mild side effects have also surfaced. More explorative, placebo-controlled and long-term clinical trials would need to be conducted in order to identify amino acid formulae that are safe and of true benefit to DMD patients.
Complex I deficiency is the most common biochemical phenotype observed in individuals with mitochondrial disease. With 44 structural subunits and over 10 assembly factors, it is unsurprising that ...complex I deficiency is associated with clinical and genetic heterogeneity. Massively parallel sequencing (MPS) technologies including custom, targeted gene panels or unbiased whole-exome sequencing (WES) are hugely powerful in identifying the underlying genetic defect in a clinical diagnostic setting, yet many individuals remain without a genetic diagnosis. These individuals might harbor mutations in poorly understood or uncharacterized genes, and their diagnosis relies upon characterization of these orphan genes. Complexome profiling recently identified TMEM126B as a component of the mitochondrial complex I assembly complex alongside proteins ACAD9, ECSIT, NDUFAF1, and TIMMDC1. Here, we describe the clinical, biochemical, and molecular findings in six cases of mitochondrial disease from four unrelated families affected by biallelic (c.635G>T p.Gly212Val and/or c.401delA p.Asn134Ilefs∗2) TMEM126B variants. We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy. Functional experimentation including viral rescue and complexome profiling of subject cell lines has confirmed TMEM126B as the tenth complex I assembly factor associated with human disease and validates the importance of both genome-wide sequencing and proteomic approaches in characterizing disease-associated genes whose physiological roles have been previously undetermined.
The sporadic form of inclusion body myositis (IBM) is the most common late-onset myopathy. Its complex pathogenesis includes degenerative, inflammatory and mitochondrial aspects. However, which of ...those mechanisms are cause and which effect, as well as their interrelations, remain partly obscured to this day. In this review the nature of the mitochondrial dysregulation in IBM muscle is explored and comparison is made with other muscle disorders. Mitochondrial alterations in IBM are evidenced by histological and serum biomarkers. Muscular mitochondrial dynamics is disturbed, with deregulated organelle fusion leading to subsequent morphological alterations and muscle displays abnormal mitophagy. The tissue increases mitochondrial content in an attempt to compensate dysfunction, yet mitochondrial DNA (mtDNA) alterations and mild mtDNA depletion are also present. Oxidative phosphorylation defects have repeatedly been shown, most notably a reduction in complex IV activities and levels of mitokines and regulatory RNAs are perturbed. Based on the cumulating evidence of mitochondrial abnormality as a disease contributor, it is therefore warranted to regard IBM as a mitochondrial disease, offering a feasible therapeutic target to be developed for this yet untreatable condition.
Extensive diagnostic delays and deferred treatment impact the quality of life of patients suffering from an idiopathic inflammatory myopathy. In-depth subtyping of patients is a necessary effort to ...engage appropriate disease management and may require specialized and elaborate evaluation of the complex spectrum of clinical and pathological disease features. Blood samples are routinely taken for diagnostic purposes, with creatine kinase measurement and autoantibody typing representing standard diagnostic tools in the clinical setting. However, for many patients the diagnostic odyssey includes the invasive and time-consuming procedure of taking a muscle biopsy. It is proposed that further implementation of blood-based disease biomarkers represents a convenient alternative approach with the potential to reduce the need for diagnostic muscle biopsies substantially. Quantification of judicious combinations of circulating cytokines could be added to the diagnostic flowchart, and growth differentiation factor 15 and C-X-C motif chemokine ligand 10 come forward as particularly good candidates. These biomarkers can offer complementary information for diagnosis indicative of disease severity, therapeutic response and prognosis.
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