Grant Duration
12/22 – 10/24

Dysferlinopathies manifest postgrowth, increase in severity with age and are associated with significant lipid accumulation in affected muscles. However, the precise mechanisms leading to alterations in intramyocellular lipid content and composition, and the eventual infiltration of intermyofiber adipocytes is unknown. It is also unclear if, and how, myocellular lipid accumulation impacts muscle function.

We have previously shown that there are significant changes in the muscle lipidome of dysferlin-deficient mice, with major changes in triglycerides and cholesterol esters. Of interest, the gene encoding DGAT2, which catalyses the terminal and only committed step in triacylglycerol synthesis, was dramatically increased in muscle of dysferlin-deficient mice.

The aim of this study was to reduce DGAT2 in skeletal muscle of dysferlin-deficient mice to prevent the accumulation of intramyocellular triglyceride and the associated impairments in muscle function.

Using muscle specific adeno-associated virus silencing (AAV shRNA), we inhibited DGAT2 protein by 51% in muscles of BLA/J mice prior to onset of myofiber adipose infiltration, and assessed whole body metabolism, fine motor skills, and muscle regeneration and function following myotoxic injury 16 weeks later. While inhibition of DGAT2 did not alter muscle triglyceride content or muscle function (as assessed by peak force), there were mild improvements in metabolism and physical functions, including increased energy expenditure, increased standing and rearing, enhanced fine motor skills (as assessed by time-to-cross balance beam), reductions in plasma lipids such as cholesterol and non-esterified fatty acids, and reduced adiposity. Following barium chloride injection, mice regenerated less large myofibers and shifted towards type IIx fibers. This was associated with a 58% reduction in peak force, compared to 64% in untreated BLA/J mice. Although this is a marginal difference, it supports the notion that Dysferlin is not needed for immediate resealing of fibers during stretch but rather protects fibers against rapid degeneration.

In conclusion, inhibiting DGAT2 in the muscles of dysferlin-deficient mice did not reduce intramyocellular triglyceride levels or significantly improve muscle function. Although it is still unclear how lipid infiltration is directly linked to the skeletal muscle pathology, eliminating fat can improve metabolic health parameters in mice with dysferlinopathies.