Hyperhomocysteinemia promotes lipid deposition in skeletal muscle.

BACKGROUND

Lipid storage myopathy (LSM) is characterized by abnormal lipid accumulation in skeletal muscle. Emerging evidence suggests that environmental factors, including the use of antidepressants such as sertraline, may trigger LSM. Given the established link between hyperhomocysteinemia (HHcy) and disrupted lipid metabolism, we investigated its potential role in skeletal muscle lipid deposition.

METHODS

We enrolled six patients with HHcy undergoing muscle biopsy and explored their clinical and pathological characteristics of skeletal muscle. The mechanistic link was explored in muscle tissues from patients through transcriptomic profiling, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzymatic assays, and validated in C2C12 myotubes.

RESULTS

Four of the six patients presented with clinical myopathic manifestations, including progressive muscle weakness and exercise intolerance, which resolved completely after B-vitamin supplementation, while abnormal skeletal muscle lipid deposition was observed in all six patients. Transcriptome and qRT-PCR analyses demonstrated a significant upregulation of the acetyl-CoA carboxylase β (ACACB) gene (p < 0.001), which encodes acetyl-CoA carboxylase 2 (ACC2), in the muscle tissues from patients. Furthermore, ACC2 protein expression was markedly elevated (p < 0.01), thereby raising cellular malonyl-CoA levels (p < 0.01). This metabolite potently inhibits carnitine palmitoyltransferase 1 (CPT1), impairing fatty acid oxidative metabolism in skeletal muscle. The key molecular cascade involving ACACB upregulation and subsequent CPT1 inhibition (p < 0.05), was further verified in C2C12 myotubes.

CONCLUSION

This study indicates that HHcy is closely associated with abnormal skeletal muscle lipid deposition. HHcy may correlate with increased ACC2 expression, which elevates malonyl-CoA levels. This, in turn, suppresses CPT1 activity and facilitates abnormal lipid accumulation in skeletal muscle.