Selective induction by statins of FAM134B-mediated sarcoplasmic reticulum (SR)-phagy degrades the SR calcium pump SERCA1 and contributes to myopathy

Summary Statins, HMG-CoA reductase inhibitors, are the most prescribed medication for lowering low-density lipoprotein cholesterol. Although statin intolerance due to statin-associated muscle symptoms (SAMS) has been a clinically important issue for decades, the molecular mechanisms of statin myopathy remain incompletely understood. To seek to clarify how statins induce myopathy, here we perform transcriptome analysis and identify FAM134B short isoform (FAM134B-S), an endoplasmic reticulum (ER)-phagy receptor, as a statin-inducible gene. FAM134B-S expression is regulated by the mevalonate pathway and sterol regulatory element-binding proteins. We further show that FAM134B plays a critical role in the regulation of skeletal muscle integrity both in the steady-state and statin-treated conditions in human iPS cell-derived myocytes and mice. Mechanistically, FAM134B-S interacts with the sarcoplasmic reticulum (SR) calcium pump SERCA1 and promotes its autophagic degradation. Collectively, our work reveals a hitherto undisclosed mechanism of statin myopathy; blocking the mevalonate pathway induces SERCA1 degradation through FAM134B-mediated SR-phagy, exerting myotoxicity. Competing Interest Statement The authors have declared no competing interest. Abbreviations - HMG-CoA - 3-hydroxy-3-methylgrutaryl coenzyme A - AAV - Adeno-associated virus - CVD - Cardiovascular disease - ER - Endoplasmic reticulum - GGOH - Geranylgeraniol - GGPP - Geranylgeranyl pyrophosphate - HMGCR - Gastrocnemius - Gas - HMG-CoA reductase - hiPSCs - Human induced pluripotent stem cells - hiPSC-MCs - hiPSC-derived myocytes - LDL - Low-density lipoprotein - MVA - Mevalonate - MLN - Mevalonolactone - Quad - Quadriceps - SAMS - Statin-associated muscle symptoms - SIM - Stain-induced myopathy - SREBP - Sterol regulatory element-binding protein - SR - Sarcoplasmic reticulum - SERCA1 - Sarcoplasmic reticulum calcium ATPase 1 - TA - Tibialis anterior - Sol - Soleus