The protective role of desmin in duchenne muscular dystrophy: Therapeutic insights

Skeletal muscles play a fundamental role in maintaining homeostasis. Composing up to 40% of the body mass in healthy individuals, skeletal muscles contain several bundles of muscle fibre rich with vascularization and innervation. The malleable structural components of skeletal muscle contribute to the overall integrity of the body. In turn, skeletal muscle is a highly dynamic tissue that has the capacity to adapt to various physiological and pathological conditions by changing its fibre size, composition and structural properties. To maintain the composition of skeletal muscle, several proteins must provide stability and integrity. Skeletal muscle health is implicated in a wide range of muscular dystrophies, which disrupt muscle homeostasis. Muscular dystrophies comprise a group of neuromuscular disorders characterized by skeletal muscle wasting. A major focus in uncovering the mechanisms involved in neuromuscular disorders has been through identifying the functional importance of various intracellular and extracellular structural elements. Currently, it is well known that dystrophin, a structural protein found on the cytoplasmic surface of the sarcolemma, is implicated in Duchenne muscular dystrophy (DMD). DMD is an X-linked genetic disorder characterized by weakness and wasting of muscles, progressive degeneration and chronic local inflammation. DMD is the result of a mutation on the dystrophin gene that leads to the absence or reduced function of dystrophin protein. Various studies investigating DMD use the mdx mouse model because it lacks dystrophin as a result of a mutation on exon 23 in the dystrophin gene (Dmd). A major focus in this field is the elucidation of compensatory mechanisms involved in adapting to the absence of dystrophin. The absence of dystrophin leads to a dysfunctional dystrophin–glycoprotein complex because dystrophin links cytoskeletal and membrane elements. The dystrophin–glycoprotein complex is essential for providing stability and rigidity, as well as for mediating interactions between the cytoskeleton, membrane and extracellular matrix. Moreover, the interactions between components of the intracellular matrix, extracellular matrix and sarcolemma are further stabilized by costameres during contraction. Therefore, a disruption in the localization between the dystrophin–glycoprotein complex and costameres results in impaired transmission of force and increased fragility (Ramaswamy et al. 2011). Another feature of dystrophic muscles contributing to progressive strength loss and fragility is markedly high prevalence of malformed myofibres (Hernández-Ochoa et al. 2015). It well-established that the phenotypes associated with dystrophic muscles are incredibly complex and have extensive implications for overall homeostasis. Additionally, DMD can lead to pulmonary morbidity and cardiovascular complications. As such, there is an urgent need for developing effective therapeutic strategies that have potential for immediate application (Selsby et al. 2016). Although various studies have investigated the role of dystrophin in DMD, little is known about the therapeutic potential of targeting intermediate filaments, which have an important role in linking sarcomeres to the extracellular matrix. The characterization of desmin as a potential therapeutic target that could attenuate muscle wasting in a DMD model is an important implication reported by Ferry et al. (2020) in The Journal of Physiology. In their study, Ferry et al. (2020) provide experimental evidence indicating that desmin, a muscle-specific, type III intermediate filament, may play important roles in locomotor muscle performance, fragility and wasting in dystrophic mdx mice. Desmin is integral to the contractile mechanism because it connects myofibrils at the Z-disk level, as well as the Z-disk to the sarcolemma. Furthermore, muscle damage has been related to a loss of desmin (Féasson et al. 2004). Ferry et al. (2020) therefore hypothesized that inactivation of the desmin gene would intensify features of muscle dystrophy. To test their hypothesis, Ferry et al. (2020) compared mdx desmin double knockout mice (DKO) with mdx mice. Interestingly, ultrastructural analysis results indicated an increase in fibrosis and degradation of sarcomere integrity in DKO mice compared to mdx mice. These findings highlight the functional importance of desmin with respect maintaining the capacity of maximal force production. To examine the impact of endogenous desmin in mdx mice, Ferry et al. (2020) measured the responsiveness of in situ tibialis anterior (TA) muscle contraction after nerve stimulations. The findings obtained from measurements of maximal tetanic isometric force and susceptibility to contraction-induced injury indicated that endogenous desmin reduced fragility in mdx mice, whereas the same effect was not observed in C57 mice. Moreover, the findings gathered from both electromyography measurements and immunohistochemical analysis further support the notion that desmin protects against worsening of fragility and decreased fatigue resistance in mdx mice. Collectively, these findings provide original evidence demonstrating the importance of desmin for preventing extreme fragility in mice lacking dystrophin. To evaluate muscle hypertrophy, a well-known dystrophic mdx feature, Ferry et al. (2020) compared muscle weight and muscle weight relative to body weight in 2-month-old mdx mice to C57 mice, as well as to DKO and DesKO mice. Body weight measurements revealed that desmin protects against muscle atrophy and is required for muscle hypertrophy in mdx mice. Moreover, an interesting finding was that LC3-II, a marker of autophagy, and the mRNA levels of Atrogin-1 and Murf1, which are key E3 ligases involved in proteolysis, did not differ between DKO and mdx mice. Ferry et al. (2020) concluded that muscle atrophy in DKO mice occurred independently from either autophagy or the ubiquitin proteasome system, the two main cellular catabolic processes. Alternatively, it may be of interest in future investigations to compare the involvement of ubiquitous calpains in initiating the degradation of muscle-specific proteins, such as desmin, between DKO and mdx mice (Féasson et al. 2004). Furthermore, another intriguing feature of the study by Ferry et al. (2020) is that they performed intramuscular injection with an adeno-associated virus (AAV) vector (AAV-Des) to deliver the desmin gene (Des) into DKO muscle. Ferry et al. (2020) employed AAV-Des to examine the potential of improving dystrophic features in mdx muscle. Interestingly, the results gathered from qPCR and western blot analyses indicated that desmin may improve muscle performance. Overall, these experimental data indicate that, in the absence of dystrophin, endogenous desmin is necessary to maintain hindlimb muscle performance and to prevent extreme fragility and exaggerated weakness. These original investigations provide an important clue towards a better understanding of the structural and functional importance of desmin in models of muscular dystrophy. Specifically, these findings highlight the unexplored protective role of desmin in attenuating dystrophic features in a mdx mice model of DMD. The findings reported in this study have important implications in the field of DMD because investigations into the molecular mechanisms of muscular dystrophy are in urgent demand. As a result of the lack of evidence demonstrating the mechanisms involved in the pathophysiology of DMD, there are very few effective therapies currently available. To develop a robust understanding of DMD induced muscle wasting, novel investigations into mechanisms regulating the structural proteins comprising muscle cell cytoskeletal architecture are needed. Ferry et al. (2020) provide interesting findings that highlight the potentially protective role of desmin in the course of the disease. These therapies can potentially be achieved through manipulating the expression of the gene encoding desmin (Des) by inducing expression of upstream transcription factors that up-regulate the expression of Des. It is therefore crucial to further elucidate the mechanisms underlying the transcriptional control of desmin expression in mdx models of DMD. Invaluable insights may be gained from these novel investigations that could prove to be extremely useful in the development of therapies targeting intracellular elements, such as desmin, as a means of attenuating dystrophic features in models of muscle dystrophy. The author apologizes for not citing all relevant articles due to reference limitations of the Journal Club format. No competing interests declared. Sole author. T.J.C is supported by an Honours Summer Research Award and a Nova Scotia Health Research Foundation Scotia Scholars Undergraduate Award (Grant Numbers: 2513).

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