Therapeutic potential of skeletal muscle plasticity and slow muscle programming for muscular dystrophy and related muscle conditions

Abstract

Duchenne muscular dystrophy (DMD) is a devastating life-limiting disease causing progressive and severe muscle wasting in boys and young men. It is simply unacceptable that ~30 years after the discovery of the culprit protein, dystrophin, there is still no cure or effective treatment. Dystrophic muscles are fragile, injury prone and compromised in their regenerative capacity. Interestingly, in DMD and in two well-characterised murine models of the disease (mdx and dko mice), fast muscle fibres are more susceptible to damage and pathological progression than slow muscle fibres, which are resistant to damage and relatively spared. Therefore, therapies that promote a slower, more oxidative phenotype could protect muscles from damage, ameliorate the dystrophic pathology and improve patient quality of life. Muscle plasticity can be achieved through exercise and/or well-described pharmacologic approaches, including activation of AMP-activated protein kinase (AMPK). Exercise has beneficial effects on muscle health, but unfortunately many patients cannot exercise, especially DMD patients confined to wheelchairs. Modulating muscle activity through low-frequency stimulation (LFS) protocols could mimic exercise to promote a slow phenotype, protect muscles from damage and enhance muscle repair. Enhancing these adaptations by combining LFS with pharmacologic modifiers of muscle phenotype potentially represents a novel therapy that could find immediate application to improve the pathology and enhance patient quality of life. Alternative approaches like anabolic agents or myostatin inhibition also have therapeutic potential, but their efficacy occurs through different mechanisms. Better understanding of the mechanisms underlying skeletal muscle adaptations to different interventions and stimuli will help optimise novel strategies to address the pathophysiology of DMD and related muscle conditions.