Duchenne muscular dystrophy | EPFL Graph Search

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms. This can result in trouble standing up. Most are unable to walk by the age of 12. Affected muscles may look larger due to increased fat content. Scoliosis is also common. Some may have intellectual disability. Females with a single copy of the defective gene may show mild symptoms. The disorder is X-linked recessive. About two thirds of cases are inherited from a person's mother, while one third of cases are due to a new mutation. It is caused by a mutation in the gene for the protein dystrophin.

Metabolic rescue of muscle and muscle stem cells in muscle disease

Peiling Luan

Duchenne muscular dystrophy (DMD), caused by the mutation of dystrophin gene, is an X-linked disorder that affects 1 in 3500 males, leading to progressive muscle degeneration and eventually resulting in premature death. Increasing evidence indicates that DMD and age-related sarcopenia share clinical hallmarks, such as decreased metabolic activity of both myofibers and muscle stem cells (MuSCs), which results in defective MuSC function and impaired muscle regeneration. In my Ph.D. thesis, I focused on manipulating mitochondrial function, such as mitophagy, and lipid metabolism, particularly sphingolipid metabolic pathways, to restore muscle and MuSC functions in DMD and age-associated sarcopenia. My thesis consists of three projects: Rescue of mitophagy improves muscle function in DMD. In this project, we identified defective mitophagy as a hallmark of muscular dystrophy. Rescue of dysfunctional mitophagy by dietary supplementation of Urolithin A (UA), a metabolite present in fruit extracts and a potent activator of mitophagy, improved muscle function in mdx mice. The beneficial effects of mitophagy restoration observed in dystrophic animals were attributed to the improvement in mitochondrial function, structural integrity of muscles, restoration of MuSC activity, and reduction in general inflammation and fibrosis. Sphingolipid depletion improves muscle regeneration during ageing. We first established the link between sphingolipid metabolism and ageing by demonstrating that sphingolipids accumulate in skeletal muscle upon aging. We reduced skeletal muscle sphingolipid accumulation by treating aged mice with myriocin, a selective inhibitor of serine pamitoyltransferase (SPT), the first and rate-limiting enzyme of sphingolipid de novo synthesis pathway. Sphingolipid depletion increased MuSC regenerative ability through enhancing the proliferation and differentiation capacities of MuSCs, ultimately leading to the prevention of age-related decline in muscle mass and function. Inhibition of sphingolipid synthesis reverts muscular dystrophy. By studying skeletal muscle transcript profiles of human muscular dystrophies, we identified upregulation of sphingolipid biosynthetic pathway as a universal feature of human patients affected with muscular dystrophy. To rescue the aberrant sphingolipid metabolism, we treated mdx mice with myriocin and showed that inhibition of sphingolipid generation enhanced muscle function, leading to amelioration of DMD. Furthermore, we uncovered a novel role of sphingolipid depletion in macrophage polarization and in reconstruction of the mdx MuSC niche, resulting in improved regenerative capacity of MuSCs. In summary, our work establishes the essential roles of mitophagy and sphingolipid metabolism in maintaining muscle and MuSC function. Restoration of mitophagy and blockade of sphingolipid generation could therefore be attractive treatment strategies to delay the progression of DMD and age-related sarcopenia.

EPFL2020

Assessment of Body Motion and Muscle Weakness

Raluca Lidia Ganea

Muscle weakness is a common symptom in elderly population and in children with Duchenne muscular dystrophy (DMD), causing impaired mobility. DMD is a devastating degenerative disease caused by a mutation in the dystrophin gene, leading to the absence of the corresponding protein. Children with DMD experience with disease progression a gradual decline in their ability to perform functional tasks. Precise methods of measurement are necessary to more accurately establish the effect of treatment and find the temporal trend in functional motor status. With regard to the aging population, it is largely recognized that there is a substantial need for an accurate health assessment. Thus, it can have significant implications for older patients' care planning and future quality of life. Despite ongoing research, the development of reliable and objective outcome measures in this population is still a major challenge. The development of these outcome measures is further complicated by certain aspects such as frailty, comorbidity, and heterogeneity in this population. The assessment of health's status in aged population and DMD children is not only useful for the prediction of health decline with age, but also for the evaluation of the outcomes of early treatments in both populations. In DMD, large research efforts are made to find efficient treatments to slow/stop the disease progression. Finding appropriate outcome measures which reflect an improvement or stabilization in functional ability of the subject is also another challenge that clinicians are currently facing. The research aims of this thesis were: (i) to provide new and accurate measures/outcomes in order to assess the effect of treatment and to determine the temporal trend in functional motor status in two types of disorders related to muscle weakness (frailty and Duchenne muscular dystrophy); (ii) to analyze relevant body movements such as postural transitions and gait in laboratory as well as in real-world conditions/environment; (iii) to compare the objective outcomes obtained by analyzing body movements to the relevant clinical scores. New objective parameters have been proposed to quantify the sit-to-stand and stand-to-sit movements. In regard to the one of the most functional demanding daily tasks which is the ability to rise from a chair (sit-to-stand transition), these parameters showed high sensitivity to change. From a clinical point of view, they separated successfully frail elderly subjects from healthy elderly subjects, as well as different evaluations of frail elderly before and after the rehabilitation program. The new parameters developed in the current study may capture more subtle functional changes that might help for prediction of adverse events during the disability development. A new algorithm was designed for detection of the sit-to-stand and stand-to-sit postural transitions patterns in real-life conditions based only on one body-worn inertial sensor. For the first time a technical validation was proposed with real-world data and its superiority compared to existing controlled validation protocols was shown. The proposed algorithm provides a simple method to detect and characterize postural transitions in healthy subjects and also in disorders such as chronic pain and frail elderly subjects. We showed that gait parameters obtained during long distance walking separated successfully the DMD patients from age-matched healthy children. The study showed the potential of such parameters to distinguish between different stages of the disease and open new perspectives for an objective assessment of the efficacy of some new therapies associated with Duchenne muscular dystrophy. We believe that these research investigations may have applicability in both clinical and research fields related to elderly, DMD children and probably other neuromuscular disorders.

EPFL2011

Molecular and cell-based therapies for muscle degenerations: a road under construction

Marco Cassano, Stefania Crippa

Despite the advances achieved in understanding the molecular biology of muscle cells in the past decades, there is still need for effective treatments of muscular degeneration caused by muscular dystrophies and for counteracting the muscle wasting caused by cachexia or sarcopenia. The corticosteroid medications currently in use for dystrophic patients merely help to control the inflammatory state and only slightly delay the progression of the disease. Unfortunately, walkers and wheel chairs are the only options for such patients to maintain independence and walking capabilities until the respiratory muscles become weak and the mechanical ventilation is needed. On the other hand, myostatin inhibition, IL6 antagonism and synthetic ghrelin administration are examples of promising treatments in cachexia animal models. In both dystrophies and cachectic syndrome the muscular degeneration is extremely relevant and the translational therapeutic attempts to find a possible cure are well defined. In particular, molecular-based therapies are common options to be explored in order to exploit beneficial treatments for cachexia, while gene/cell therapies are mostly used in the attempt to induce a substantial improvement of the dystrophic muscular phenotype. This review focuses on the description of the use of molecular administrations and gene/stem cell therapy to treat muscular degenerations. It reviews previous trials using cell delivery protocols in mice and patients starting with the use of donor myoblasts, outlining the likely causes for their poor results and briefly focusing on satellite cell studies that raise new hope. Then it proceeds to describe recently identified stem/progenitor cells, including pluripotent stem cells and in relationship to their ability to home within a dystrophic muscle and to differentiate into skeletal muscle cells. Different known features of various stem cells are compared in this perspective, and the few available examples of their use in animal models of muscular degeneration are reported. Since non coding RNAs, including microRNAs (miRNAs), are emerging as prominent players in the regulation of stem cell fates we also provides an outline of the role of microRNAs in the control of myogenic commitment. Finally, based on our current knowledge and the rapid advance in stem cell biology, a prediction of clinical translation for cell therapy protocols combined with molecular treatments is discussed.

Frontiers Research Foundation2014