The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

“… 60 UA induction of mitophagy could potentially mediate its anti-inflammatory effect, as removing dysfunctional mitochondria reduces the production of reactive oxygen species (ROS) and the release of mtDNA and cardiolipins, known triggers of inflammatory responses. 50 , 61 In turn, UA-mediated reduction of inflammatory markers could contribute to blunting their negative regulation of mitochondrial biogenesis effectors, such as PGC1a and SIRT1, thereby allowing the generation of new mitochondria. 61 , 62 How UA impacts both mitochondrial health and inflammation is an intriguing question that warrants in-depth mechanistic studies in more suited experimental models.…”

“… 50 , 61 In turn, UA-mediated reduction of inflammatory markers could contribute to blunting their negative regulation of mitochondrial biogenesis effectors, such as PGC1a and SIRT1, thereby allowing the generation of new mitochondria. 61 , 62 How UA impacts both mitochondrial health and inflammation is an intriguing question that warrants in-depth mechanistic studies in more suited experimental models.…”

A genome-scale metabolic model of Drosophila melanogaster for integrative analysis of brain diseases

“…Of the enriched disorders, ‘Duchenne muscular dystrophy’ is characterized by mitochondrial dysfunction and impaired mitophagy. Increased inflammation occurs due to the defective mitochondria, and it further triggers disease pathology corresponding to muscle damage and increased fibrosis in patients [128]. Similarly, Charcot-Marie-Tooth disease, which is a commonly inherited neurological disorder, leads to severe muscular deficits [129, 130].…”

Utilization of T1-Mapping for the pelvic and thigh muscles in Duchenne Muscular Dystrophy: a quantitative biomarker for disease involvement and correlation with clinical assessments

“…The MRI technique such as MRS or Dixon that is used to quantify FF will be included in our next study. Second, although the degree of skeletal muscle edema in DMD patients is relatively mild [ 9 , 20 ], we have not exclude the influence of inflammation/edema if these events happen parallel to fatty degenerations, which may represent a bias for fat infiltration monitoring based on global T1-value. Third, intramuscular fat infiltration is the main disease process of DMD, yet it also can be observed in other situations like obesity [ 38 , 39 ].…”

“…Although the disease remains incurable so far, a comprehensive and accurate assessment of disease status is crucial for implementing of treatment measures that can delay the disease progression and improve the life quality of DMD patients [ 5 , 6 ]. Clinical assessment methods such as manual muscle testing, range of joint motion, timed functional tests, motor function scales have been widely applied to evaluate the disease status of DMD patients [ 7 – 9 ]. However, the main disadvantages of these methods are unquantifiable, low repeatability, and insufficient accuracy.…”