High dietary fat causes muscle structural breakdown, mitochondrial dysfunction, and contractile deficits in the absence of carnitine palmitoyltransferase 2.

Carnitine palmitoyltransferase 2 (CPT2) deficiency is an inherited autosomal recessive disorder of fatty acid oxidation, which commonly manifests in adolescences and adulthood as muscle weakness and recurrent rhabdomyolysis, limiting physical activity and compromising quality of life. Despite the recognition and avoidance of known triggers such as exercise, fasting, and stress, many patients suffer unexplained periodic episodes of muscle breakdown. While avoidance of fatty meals is recommended, the impact of high-fat consumption alone on muscle biology of CPT-deficient patients is not well defined. Mice with muscle specific CPT2-deletion (Cpt2Sk-/-) and control littermates, were placed on control or high-fat diet (HFD) (60% kcal) for up to 8 weeks. Muscle contractility, transcriptional and protein signatures, mitochondrial metabolic capacity, and histopathology were determined. After 8 weeks on the diet, Cpt2Sk-/- ex vivo muscle force production was significantly reduced by high-fat feeding in the glycolytic EDL and oxidative soleus muscles. In response to HFD, Cpt2Sk-/- muscle mitochondrial respiratory capacity was significantly reduced, despite increased mitochondrial biogenesis, across various muscles. Importantly, HFD further deteriorated the structural integrity of oxidative soleus muscle in CPT2-deficient mice, characterized by reduced fiber size and the presence of ragged red fibers. Together, these data indicate that chronic high dietary fat intake exacerbates the underlying mitochondrial and myopathic dysfunction caused by CPT2 deficiency. This diet-induced worsening of muscle pathology may provide a mechanistic explanation for the symptom exacerbation experienced by individuals with CPT2 deficiency following fatty food consumption.