Muscular Dystrophies and Cancer Cachexia: Similarities in Chronic Skeletal Muscle Degeneration

Abstract

Muscular dystrophies (MDs) are inheritable diseases caused by mutations in specific genes encoding muscle proteins and characterized by progressive muscle wasting and weakness. MDs are classified into nine main categories, encompassing approximately 30 different diseases. Duchenne muscular dystrophy and Becker muscular dystrophy (DMD and BMD) are the most commonly diagnosed neuromuscular disorders, affecting respectively~1/3500 and 3-6/100,000 male infants worldwide. DMD is characterized by absence of dystrophin function due to complete loss of expression or to the presence of a non-functional dystrophin protein in muscle tissue, while a semi-functional dystrophin isoform is typically present in BMD. Lack of dystrophin function in MDs induces myofiber damage, causing persistent cycles of degeneration/regeneration, exhaustion of regenerative potential and fibrosis, and resulting in muscle degeneration. Cancer cachexia is a multifactorial syndrome characterized by severe body weight loss and muscle degenerative atrophy. Up to 80% of cancer patients show cachexia, and the syndrome has been estimated to causẽ 2 million of deaths per year. This cancer-related muscle wasting is mediated by pro-inflammatory cytokines and tumor-released mediators able to activate specific catabolic pathways in muscle tissue. MDs and cancer-associated cachexia (CAC) share some peculiar features, including systemic and muscle-specific inflammation, alteration of myogenic potential, ultrastructural abnormalities, and dysfunction of the dystrophin glycoprotein complex (DCG). This review focuses on the pathophysiological comparison between these two chronic muscle degenerative conditions and discusses the most relevant and promising therapeutic strategies considered so far.3 of 10 destabilization include hypoglycosylation of α-dystroglycan (α-DG), which is observed in many MDs and causes a reduction of DGC binding capacity to the ECM proteins [2,14].

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

“…Accordingly, cisplatin administration to healthy rats can reproduce some of the alterations typical of cancer cachexia, including body weight loss, adipose tissue remodeling, skeletal muscle wasting, and weakness. Furthermore, it is also well known that molecular mechanisms controlling muscle wasting in chemotherapy and cancer share common features with pathophysiology of other relevant muscle neurodegenerative such as muscular dystrophies [3,4]. The animal model commonly used to study the derangements specifically associated with chemotherapy and for testing new therapies for cachexia is the rat or mouse intraperitoneally treated with cisplatin (1-3 mg/kg) for 3-4 consecutive days to induce weight loss without over-toxicity [5][6][7][8][9].…”

Neuromuscular junctions are stable in patients with cancer cachexia

“…At present, the consensus definition of cancer cachexia confirms loss of skeletal muscle as a key feature of the condition (3), largely mediated by proinflammatory cytokines and tumor-associated mediators, resulting in the activation of catabolic pathways in skeletal muscle (4). In this regard, cancer cachexia shares many of the muscle-specific and systemic inflammatory pathways common to the muscular dystrophies (5,6).…”

Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy

“…Interestingly, DMD shares several features with other conditions characterized by loss of muscle mass and strength, specifically age-related sarcopenia [5] and cancer-associated cachexia, a multifactorial syndrome affecting large part of cancer patients [6]. Systemic and muscle inflammation, oxidative stress, ultrastructural abnormalities, alteration of the DAPC, and loss of muscle precursor cells are common hallmarks of DMD, sarcopenia and cachexia [7][8][9], suggesting that common approaches could be thought of to treat these conditions.…”