Desmin prevents muscle wasting, exaggerated weakness and fragility, and fatigue in dystrophic mdx mouse

Abstract

Key points Desmin, similar to dystrophin, is associated with costameric structures bridging sarcomeres to the extracellular matrix. Deletion of the desmin gene in mdx mice [double knockout (DKO) mice] induces marked muscle weakness and fatigue resistance compared to mdx mice. Muscle fragility (higher susceptibility to contraction‐induced injury) was also aggravated in DKO mice compared to mdx mice. By contrast to mdx mice, the DKO mice did not undergo muscle hypertrophy. Desmin cDNA transfer with adeno‐associated virus in newborn mdx mice reduced muscle weakness. Overall, desmin plays important and beneficial roles in muscle wasting, performance and fragility in dystrophic muscle. Abstract Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease caused by dystrophin deficiency. Desmin, similar to dystrophin, is associated with costameric structures bridging sarcomeres to the extracellular matrix that contributes to muscle function. In the present study, we attempted to provide further insight into the roles of desmin, for which the expression is increased in the muscle from the mouse mdx DMD model. We show that a deletion of the desmin gene (Des) in mdx mice [double knockout (DKO) mice, mdx:desmin–/–] induces a marked muscle weakness; namely, a reduced absolute maximal force production and increased fatigue compared to that in mdx mice. Fragility (i.e. higher susceptibility to contraction‐induced injury) was also aggravated in DKO mice compared to mdx mice, despite the promotion of supposedly less fragile muscle fibres in DKO mice, and this worsening of fragility was related to a decreased muscle excitability. Moreover, in contrast to mdx mice, the DKO mice did not undergo muscle hypertrophy, as indicated by smaller and fewer fibres, with a reduced percentage of centronucleated fibres, potentially explaining the severe muscle weakness. Notably, Desmin cDNA transfer with adeno‐associated virus in newborn mdx mice improved specific maximal force normalized to muscle weight. Overall, desmin plays important and beneficial roles in muscle wasting, performance and fragility in dystrophic mdx mice, which differ, at least in part, from those observed in healthy muscle.

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

“…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.…”

“…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.…”

“…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.…”

“…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 .…”

“…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.…”