Metabolic rescue of muscle and muscle stem cells in muscle disease

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.