Sphingolipids mediate lipotoxicity in muscular dystrophies

and myosteatosis (Rodriguez-Cruz et al. 2015). Could the Metabaging Cycle, i.e. local myoblast and myofiber inflammation leading to local IR and dyslipidemia, ultimately leading to a lipotoxic vicious cycle that gradually impairs systemic health during aging (Ma et al. 2022), occur in both MetS and muscular dystrophy patients via sphingolipid-mediated toxicity? More work will be needed to unravel these common threads weaving the complex tapestry of metabolic dysfunction in muscle disorders.

A c c e p t e d M a n u s c r i p t Muscular dystrophies are a genetically diverse group of muscular diseases that share similar clinical symptoms of progressive weakness and death of skeletal muscle cells during development.
Over 30 different disorders are classified as muscular dystrophies, including Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy, and myotonic muscular dystrophy -all of which are themselves diverse in the age of onset, the speed of pathogenesis, the degree of weakness, the exact muscle groups that are affected, and the gene mutations that are involved (Datta et al. 2020).
Nevertheless, most if not all muscular dystrophies are caused by inherited or spontaneous genetic mutations that implicate aberrant muscle protein expression, e.g. dystrophin for BMD and DMD, and dysferlin for distal muscular dystrophy.
Thus, it stands to reason to attempt to treat all muscular dystrophies with gene and cell therapies that correct the particular genetic mutation latent within the patient. Efforts in this area include viral transduction of microdystrophin, delivery of CRISPR gene editors or antisense RNAs that suppress pathogenic gene expression, or myoblast transfer therapy, i.e. autologous injections of gene-corrected myogenic stem cells to mediate normal muscle regeneration. However, these gene and cell therapeutic approaches are mired in two quandaries. Firstly, the huge diversity of mutations within each type of muscular dystrophy complicates the applicability of off-the-shelf therapies.
Secondly, the small numbers of patients available for each genotype of muscular dystrophy complicates clinical trial design. While these problems are being solved, other pharmacological solutions have also been developed to ameliorate muscular dystrophies, including anabolic steroids, anticonvulsants, calcium channel blockers, and immunosuppressive corticosteroids. Such nongenetic drug treatments could greatly help patients where gene therapies are not suitable or available yet, and could still complement gene therapies in the future.
While genetically diverse, all muscular dystrophies commonly involve myofiber degeneration, aberrant calcium homeostasis, cell death, inflammation and fibrosis (Deconinck et al. 2007). A c c e p t e d M a n u s c r i p t myriocin inhibition of SPT reduced the high levels of sphinganine, dihydroceramides and long-chain ceramides, thereby improving calcium homeostasis, reducing intramuscular inflammation and inflammation-induced cycles of muscle regeneration. Notably, SPT inhibition shifted the balance from pro-inflammatory M1 macrophages towards anti-inflammatory M2 macrophages, and suppressed fibrosis mediated by PDGFRα+ fibro-adipogenic precursors (FAPs) in the tibialis anterior muscles, diaphragm muscles and cardiac muscles, thereby preventing the loss of muscle strength, respiratory failure and cardiac failure in DMD. At low concentrations (which avoided the hepatotoxicity occasionally observed in rodents), myriocin still rescued these mdx mouse phenotypes more effectively than a corticosteroid drug (Figure 1). This groundbreaking study demonstrated that inhibition of sphingolipid biosynthesis can target multiple common mechanisms in muscular dystrophies simultaneously, indicating that this metabolic pathway could represent a series of druggable targets for the development of novel treatments against muscular dystrophies.
As these findings begin to spark a new wave of exciting developments in therapies against muscular dystrophies, it is worth noting that the fatty acid-derived ceramides have long been suspected as a driver of lipotoxicity in the metabolic syndrome (MetS) during human aging.