Duchenne muscular dystrophy (DMD) is characterized by rapid wasting of skeletal muscle. Mitochondrial dysfunction is a well-known pathological feature of DMD. However, whether mitochondrial dysfunction occurs before muscle fiber damage in DMD pathology is not well known. Furthermore, the impact upon heterozygous female mdx carriers (mdx/+), who display dystrophin mosaicism, has received little attention. We hypothesized that dystrophin deletion leads to mitochondrial dysfunction, and that this may occur before myofiber necrosis. As a secondary complication to mitochondrial dysfunction, we also hypothesized metabolic abnormalities prior to the onset of muscle damage. In this study, we detected aberrant mitochondrial morphology, reduced cristae number, and large mitochondrial vacuoles from both male and female mdx mice prior to the onset of muscle damage. Furthermore, we systematically characterized mitochondria during disease progression starting before the onset of muscle damage, noting additional changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice that were exacerbated with high-fat diet feeding. Lastly, inhibition of the strong autophagic program observed in adolescent mdx male mice via administration of the autophagy inhibitor leupeptin did not improve skeletal muscle pathology. These results are in line with previous data and suggest that before the onset of myofiber necrosis, mitochondrial and metabolic abnormalities are present within the mdx mouse.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Background The patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement. Main text Through this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations. Conclusion Further insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments.

Background:Muscular dystrophies are a diverse family of genetic and hereditary disorders manifested primarily by the progressive wasting of skeletal muscle. Duchenne muscular dystrophy (DMD), the most common muscular dystrophy, has no cure, with most treatments seeking to mitigate symptoms. Emerging gene or stem cell therapies hold promise, although widespread clinical adoption may not occur for quite some time. There remains a need for alternative strategies, including drug and lifestyle combination-based therapies, and to continue furthering understanding the physiological effects of dystrophin gene mutations. Mitochondrial dysfunction is well known as a pathological feature of DMD. However, whether mitochondrial dysfunction is a cause or the consequence of DMD is not well known. We hypothesized that dystrophin deletion would lead to mitochondrial and metabolic abnormalities prior to the onset of observable muscle damage.Methods:Utilizing the commonly employed muscular dystrophy mouse model, C57BL/10ScSn-Dmdmdx/J (mdx), we sought to determine how the loss of dystrophin effects mitochondria and metabolism in both male and female mdx mice. We also treated male mdx mice with an autophagy inhibitor, leupeptin, to investigate its potentially impact on mdx pathology.Results:We detected, via electron microscopy, aberrant mitochondrial morphology, reduced cristae numbers per area of mitochondria, and large mitochondrial vacuoles from both two-week-old male and 24-week-old female mdx carrier mice, prior to the onset of visible muscle fiber damage. We systematically characterized mitochondria during disease progression starting before the onset of gross muscle fiber damage noting changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice (heterozygous mdx/+) that was exacerbated with high-fat diet feeding. Lastly, we found autophagy inhibition did not improve pathology in mdx male mice.Conclusions:Our results suggest that prior to the onset of visible muscle damage, mitochondrial and metabolic abnormalities are present within the mdx mouse.