Circulating Biomarkers in Muscular Dystrophies: Disease and Therapy Monitoring

Abstract

Muscular dystrophies are a group of inherited disorders that primarily affect the muscle tissues. Across the muscular dystrophies, symptoms commonly compromise the quality of life in all areas of functioning. It is well noted that muscular dystrophies need reliable and measurable biomarkers that will monitor the progress of the disease and evaluate the potential therapeutic approaches. In this review, we analyze the current findings regarding the development of blood-based circulating biomarkers for different types of muscular dystrophies. We emphasize those muscular dystrophies that gained particular interest for the development of biomarkers, including Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy types 1 and 2, Ullrich congenital muscular dystrophy, congenital muscular dystrophy type 1A, Facioscapulohumeral muscular dystrophy, and limb-girdle muscular dystrophy types 2A, 2B, 2C, and 2D, recently renamed as limb-girdle muscular dystrophy R1 calpain3-related, R2 dysferlin-related, R5 g-sarcoglycan-related, and R3 a-sarcoglycan-related. This review highlights the up-to-date progress in the development of biomarkers at the level of proteins, lipids, and metabolites, as well as micro-RNAs (miRNAs) that currently are the main potential biomarker candidates in muscular dystrophies.Muscular dystrophies are a heterogeneous group of inherited genetic muscle disorders affecting both children and adults. Currently, more than 50 distinct types of muscular dystrophies have been identified that are inherited in an autosomal dominant, autosomal recessive, or X-linked fashion. Very rarely, muscular dystrophy can occur sporadically. They all share similar clinical and pathological characteristics, including skeletal muscle weakness, wasting, and degeneration. 1 Different mutations in a variety of genes are associated with the phenotype of each muscular dystrophy. 1 The pathology of each disorder differs, reflecting various clinical characteristics, including the groups of primarily affected muscles, the degree of weakness, the time of onset, and the rate of progression. For most of the muscular dystrophies, diagnosis is well established; however, additional disease parameters, such as the progression of the disease and the response to therapeutic interventions, remain uncharacterized. This has resulted in a pressing need for the development of reliable and measurable biomarkers for both the monitoring of the disorder and the response to therapeutic approaches that concern this family of disorders.Biomarkers are measurable indicators of normal or pathogenic conditions or pharmacological responses to a therapeutic intervention.

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1

“…In recent years, emphasis has been placed on examining the potential use of circulating miRNAs as a promising tool for the diagnosis and monitoring of various diseases, including muscular dystrophies. 15 , 51 Although there are several studies focusing on the development of biomarkers in muscular dystrophies, few reports exist regarding the use of such circulating miRNAs as biomarkers for DM1. 11 , 12 , 13 , 14 , 23 , 24 Initially, nine miRNAs were found to be deregulated in plasma of DM1 patients compared to control subjects and suggested as diagnostic biomarkers for DM1.…”

Strain and sex differences in somatosensation and sociability during experimental autoimmune encephalomyelitis

“…Dysferlin is one of six ferlins involved in calcium-mediated cell dynamics necessary for muscle fiber repair ( Bulankina and Thoms, 2020 ). In humans, mutations to ferlin proteins had been implicated in multiple myopathies ( Bulankina and Thoms, 2020 ; Cardenas et al., 2016 ; Koutsoulidou and Phylactou, 2020 ; Patel et al., 2017 ). More specifically, mutations to DYSF can cause an array of muscle diseases collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2 ​B and Miyoshi myopathy ( Bulankina and Thoms, 2020 ; Cardenas et al., 2016 ; Koutsoulidou and Phylactou, 2020 ; Patel et al., 2017 ).…”

“…In humans, mutations to ferlin proteins had been implicated in multiple myopathies ( Bulankina and Thoms, 2020 ; Cardenas et al., 2016 ; Koutsoulidou and Phylactou, 2020 ; Patel et al., 2017 ). More specifically, mutations to DYSF can cause an array of muscle diseases collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2 ​B and Miyoshi myopathy ( Bulankina and Thoms, 2020 ; Cardenas et al., 2016 ; Koutsoulidou and Phylactou, 2020 ; Patel et al., 2017 ). At 6 months of age, SJL mice develop spontaneous myopathy as determined by histology, muscle wasting (body weight loss), tail-pinching, open-field and grip tests, and decreased soleus muscle force ex vivo ( Rayavarapu et al., 2010 ; Weller et al., 1997 ; Bittner et al., 1999 ; Vafiadaki et al., 2001 ).…”

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

“…Clinical assays based on marker molecules, such as DNA, miRNA, metabolites, lipids and/or proteins [ 43 , 146 , 168 ], should on the one hand be highly specific, robust, sensitive and cost-effective and on the other hand exhibit ideally only a minimum susceptibility to interference by gender, age, ethnicity, nutrition, lifestyle and circadian rhythm [ 250 ]. User-friendly biomarker tests could be highly useful to improve prenatal analysis, new-born screening and estimating disease initiation in order to decisively reduce the time between observation of initial symptoms and consolidated differential diagnosis [ 156 , 281 ].…”

“…Both biological fluids contain large and complex proteomes that are suitable for the routine diagnostic analysis of body-wide health status [ 107 , 238 ]. Promising new biofluid markers of Duchenne muscular dystrophy include fibronectin, titin fragments, fatty acid–binding protein FABP3, malate dehydrogenase MDH2, the inflammation-inducible plasma marker haptoglobin, carbonic anhydrase CA3, myosin light-chain MLC3 and matrix metalloproteinase MMP9 [ 14 , 168 , 194 , 231 , 305 , 323 ]. Some of these markers can now be validated in a number of new therapeutic applications [ 5 ].…”