Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease that causes severe loss of muscle mass and function in young children. Promising therapies for DMD are being developed, but the long lead times required when using clinical outcome measures are hindering progress. This progress would be facilitated by robust molecular biomarkers in biofluids, such as blood and urine, which could be used to monitor disease progression and severity, as well as to determine optimal drug dosing before a full clinical trial. Many candidate DMD biomarkers have been identified, but there have been few follow-up studies to validate them. This Review describes the promising biomarkers for dystrophic muscle that have been identified in muscle, mainly using animal models. We strongly focus on myonecrosis and the associated inflammation and oxidative stress in DMD muscle, as the lack of dystrophin causes repeated bouts of myonecrosis, which are the key events that initiate the resultant severe dystropathology. We discuss the early events of intrinsic myonecrosis, along with early regeneration in the context of histological and other measures that are used to quantify its incidence. Molecular biomarkers linked to the closely associated events of inflammation and oxidative damage are discussed, with a focus on research related to protein thiol oxidation and to neutrophils. We summarise data linked to myonecrosis in muscle, blood and urine of dystrophic animal species, and discuss the challenge of translating such biomarkers to the clinic for DMD patients, especially to enhance the success of clinical trials.

Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity

“…Serum creatine kinase levels reflect the degree of muscle fibre damage and are usually normal or only slightly raised in FSHD ( 1 ). By comparison, DMD generally exhibits high serum creatine kinase levels with severe pathology in many muscles ( 54 ). This is accompanied by a robust regenerative response initially in DMD: for example, the proportion of regenerating fibres expressing developmental MyHC isoforms varied from 38 to 47% in quadriceps biopsies from four DMD patients aged 4–13 years ( 55 ), 24–33% in muscle biopsies from five DMD patients aged 4.3–8.2 years ( 20 ) and a mean of 32% in muscle biopsies from three DMD patients aged 3.3–6.8 years ( 56 ).…”

The Universal Soldier: Enzymatic and Non-Enzymatic Antioxidant Functions of Serum Albumin

“…It is known that in chronic liver and kidney diseases, as well as in diabetes mellitus, the percentage of cysteinylated albumin (Cys34-S-S-Cys) is markedly increased [ 116 ]. In recent years, it has been shown that oxidised albumin can be a biomarker of the severity of such diseases as hyperparathyroidism [ 152 ], acute ischemic stroke [ 153 ], Parkinson’s disease [ 154 ], Alzheimer’s disease [ 155 ], Duchenne muscular dystrophy [ 156 ], etc.…”

The Dystrophin Node as Integrator of Cytoskeletal Organization, Lateral Force Transmission, Fiber Stability and Cellular Signaling in Skeletal Muscle

“…Primary abnormalities in caveolin-3 are associated with certain forms of muscular dystrophy and the altered expression of this protein is postulated to also play a pathophysiological role in dystrophinopathy [ 39 ]. Importantly, new findings on the underlying mechanisms of dystrophic alterations are crucial for the identification of robust and disease-specific biomarker molecules [ 40 , 41 , 42 , 43 ] and the development of novel diagnostic approaches [ 44 ], as well as the design of innovative therapies to restore the dystrophin complex and counteract secondary aspects involved in progressive muscle wasting [ 45 , 46 , 47 , 48 , 49 ].…”