Adenylosuccinic acid therapy ameliorates murine Duchenne Muscular Dystrophy

Abstract

Arising from the ablation of the cytoskeletal protein dystrophin, Duchenne Muscular Dystrophy (DMD)is a debilitating and fatal skeletal muscle wasting disease underpinned by metabolic insufficiency. The inability to facilitate adequate energy production may impede calcium (Ca 2+ ) buffering within, and the regenerative capacity of, dystrophic muscle. Therefore, increasing the metabogenic potential could represent an effective treatment avenue. The aim of our study was to determine the efficacy of adenylosuccinic acid (ASA), a purine nucleotide cycle metabolite, to stimulate metabolism and buffer skeletal muscle damage in the mdx mouse model of DMD. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were treated with ASA (3000 µg.mL −1 ) in drinking water. Following the 8-week treatment period, metabolism, mitochondrial density, viability and superoxide (O 2 − ) production, as well as skeletal muscle histopathology, were assessed. ASA treatment significantly improved the histopathological features of murine DMD by reducing damage area, the number of centronucleated fibres, lipid accumulation, connective tissue infiltration and Ca 2+ content of mdx tibialis anterior. These effects were independent of upregulated utrophin expression in the tibialis anterior. ASA treatment also increased mitochondrial viability in mdx flexor digitorum brevis fibres and concomitantly reduced o 2 − production, an effect that was also observed in cultured immortalised human DMD myoblasts. Our data indicates that ASA has a protective effect on mdx skeletal muscles.

Sodium nitrate co-supplementation does not exacerbate low dose metronomic doxorubicin-induced cachexia in healthy mice

“…All histological protocols were performed as described by us previously 37 , 78 . To determine whether LDM DOX had atrophic effects on skeletal muscle and subsequently, whether DOX + SN either exacerbated or rescued any such atrophy, we next assessed the hindlimb muscle, TA histologically.…”

“…a total of at least 500 fibres per section) in each of those areas. The CSA of these fibres was determined as described by us previously 37 , 78 .…”

“…All western blotting protocols were performed as previously described by us 78 , 80 . Since both DOX and SN are notorious producers of ROS 64 , 81 , we next investigated the effect of DOX and DOX + SN treatment on molecular markers of oxidative stress related damage, downstream anti-oxidant response targets and mitochondrial content and remodelling/biogenesis.…”

Duchenne Muscular Dystrophy (DMD) Treatment: Past and Present Perspectives

“…Recently, ASA or adenylo-succinic acid improved the status of the TA muscles in mdx mice after administration of this compound in the drinking water. This molecule regulated the expression of the utrophin protein and hence greatly reduced the damaged area [61].…”

The Failed Clinical Story of Myostatin Inhibitors Against Duchenne Muscular Dystrophy: Exploring the Biology Behind the Battle

“…Notwithstanding, type II fibres can produce significant amounts of reactive oxygen species (ROS) during explosive, high-intensity activation which drives xanthine oxidase activity through the degradation of purine nucleotides: the net result is a rapid and intense ROS production[51]. DMD mitochondria are notoriously dysfunctional and produce appreciably less adenosine triphosphate (ATP)[52][53][54] but more ROS[53,55,56], placing stress on the anaerobic energy systems, which further drives cytosolic ROS production (i.e. through xanthine oxidase, amongst other ROS producing enzymes).…”