Biology subjects

Brault, J. J.

Publications and source records attributed to Brault, J. J..

3 recordsLinked to original sources

bioRxiv2025

Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome

BackgroundBarth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) remodeling and mitochondrial function. While cardiac manifestations of BTHS are well characterized, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood. MethodsWe investigated neuromuscular and mitochondrial alterations in a novel murine model (TazPM) carrying a patient-derived D75H point mutation in Tafazzin. This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fiber composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting, and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signaling was assessed by western blotting. ResultsMale TazPM mice exhibited elevated monolysocardiolipin and reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, smaller muscle fibers of all types, and a shift toward fast-twitch type 2B fibers, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodeling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine, and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signaling pathways were markedly activated, including phosphorylation of eIF2, increased CHOP, DELE1, p53 expression, and altered Wnt/{beta}-catenin signaling components. ConclusionsDeficiency of Tafazzin enzymatic activity in skeletal muscle is sufficient to result in widespread neuromuscular remodeling, including fiber size/type shifts, motor unit loss, NMJ dysregulation, and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signaling disruptions.

cell biology↗

bioRxiv2025

Loss of adenylosuccinate synthetase 1 in mice recapitulates features of ADSS1 myopathy

ADSS1 myopathy is an ultra-rare congenital myopathy characterized by progressive cardiac and skeletal muscle degeneration with childhood to adolescent onset. This autosomal recessive disease is caused by mutations in the ADSS1 gene, encoding the enzyme adenylosuccinate synthetase (AdSS1). AdSS1 plays a critical role in the adenine nucleotide cycle, which is important for energy metabolism in muscle cells. Enzymatic defects, engendered by loss-of-function mutations in ADSS1, lead to a bottleneck in the adenine nucleotide cycle, causing metabolic dysfunction which ultimately results in progressive muscle weakness, mobility impairment, and respiratory and cardiac dysfunction, often requiring the use of a ventilator. Despite its debilitating nature, there are currently no cures or targeted treatments available, and little research into possible therapeutic strategies has been done. With a limited patient profile encompassing fewer than 200 known patients worldwide, establishing a mouse model for ADSS1 myopathy is critical to understanding its pathogenesis and for developing future therapies. Here, we present and characterize the first mouse model of ADSS1 myopathy - a constitutive Adss1 knockout model - by (1) defining its natural history, (2) exploring its metabolic pathomechanisms, and (3) characterizing its histopathological features. We find that Adss1KO/KO mice have subtle motor deficits and present with histopathological features consistent with patient phenotypes. Overall, we show that despite a relatively mild phenotype, this novel mouse model has quantifiable pathological features that can be used to develop therapies for, and further probe pathophysiology of, ADSS1 myopathy.

genetics↗

bioRxiv2019

Effects of fasting induced carbohydrate depletion on murine ischemic skeletal muscle function.

Stored muscle carbohydrate supply and energetic efficiency constrain muscle functional capacity during exercise and are influenced by common physiological variables (e.g. age, diet, and physical activity level). Whether these constraints affect overall functional capacity or the timing of muscle energetic failure during acute ischemia is not known. We interrogated skeletal muscle contractile properties in two anatomically distinct hindlimb muscles that have well characterized differences in energetic efficiency (locomotory-extensor digitorum longus (EDL) and postural-soleus muscles) under conditions of reduced carbohydrate supply. 180 mins of acute ischemia resulted in complete energetic failure in all muscles tested, indicated by: loss of force production, substantial reductions in total adenosine nucleotide pool intermediates, and increased adenosine nucleotide degradation product - inosine monophosphate (IMP). These changes occurred in the absence of apparent myofiber structural damage assessed histologically by both transverse section and whole mount. Restriction of the available intracellular carbohydrate pool by fasting (~50% decrease in skeletal muscle) did not significantly alter the timing to muscle functional impairment or affect the overall force/work capacities of either muscle type. Fasting did cause rapid development of passive tension in both muscle types, which may have implications for optimal timing of reperfusion or administration of precision therapeutics.

physiology↗