Loss of carnitine palmitoyltransferase 2 (CPT2) resulted in a shift from an oxidative metabolic profile to one that more closely resembles glycolytic metabolism in a long chain fatty acid oxidation disorder (LCFAOD) mouse model, according to the results of a new study published in Molecular Metabolism.

The authors showed that the soleus muscle (which is typically an oxidative muscle) in mice with a CPT2 deletion displayed modified metabolic rate, proteome, and oxidative phosphorylation complex assembly similar to those of glycolytic muscles and was mismatched from control soleus muscles.

“Taken together, these data suggest that when substrate-supported max respiratory capacity (JO2) and sensitivity are analyzed as a whole, the overall metabolic profile of Cpt2Sk-/- mitochondria isolated from oxidative muscle reflects that of glycolytic mitochondria,” the authors said.

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Despite these changes in energy metabolism, there was no changes induced in myosin heavy chain (MyHC) isoform composition. The soleus muscles in the study showed predominantly MyHC-β and MyHC-2A proteins, which correspond to slow, oxidative type 1 and fast, oxidative-glycolytic type 2a fibers, respectively. These compositions did not change in the muscles that lost CPT2 enzyme function.

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“These results show that loss of [mitochondrial long chain fatty acid oxidation] capacity in skeletal muscle via deletion of CPT2 does not trigger fiber type switching as defined by changes in myosin heavy chain isoform composition,” the authors explained.

The soleus muscle in mice with a CPT2 deletion showed an increased reliance on pyruvate and succinate as energy substrates compared to control soleus muscles. The reliance on these energy substrates was similar to levels seen in the glycolytic extensor digitorum longus muscles. Despite these adaptations, the CPT2-deficient mice still displayed exercise intolerance through poor treadmill performance.

The authors hypothesized that the adaptations may be sufficient for low-intensity physical activities, however. “Thus, impairments in fatty acid oxidation will shift energy metabolism without changing myosin heavy chain structure, resulting in a metabolic-contractile mismatch,” they said.

During the study, CPT2 skeletal muscle-specific conditionally deficient mice (Cpt2Sk-/-) were generated to test the results of the loss of CPT2 function. Littermates who were not Cpt2Sk-/- were used as controls.


Pereyra AS, Lin CT, Sanchez DM, et al. Skeletal muscle undergoes fiber type metabolic switch without myosin heavy chain switch in response to defective fatty acid oxidation. Mol Metab. Published online February 9, 2022. doi:10.1016/j.molmet.2022.101456