title: Skeletal muscle damage and impaired regeneration due to LPL-mediated lipotoxicity.
abstract: According to the concept of lipotoxicity, ectopic accumulation of lipids in non-adipose tissue induces pathological changes. The most prominent effects are seen in fatty liver disease, lipid cardiomyopathy, non-insulin-dependent diabetes mellitus, insulin resistance and skeletal muscle myopathy. We used the MCK(m)-hLPL mouse distinguished by skeletal and cardiac muscle-specific human lipoprotein lipase (hLPL) overexpression to investigate effects of lipid overload in skeletal muscle. We were intrigued to find that ectopic lipid accumulation induced proteasomal activity, apoptosis and skeletal muscle damage. In line with these findings we observed reduced Musculus gastrocnemius and Musculus quadriceps mass in transgenic animals, accompanied by severely impaired physical endurance. We suggest that muscle loss was aggravated by impaired muscle regeneration as evidenced by reduced cross-sectional area of regenerating myofibers after cardiotoxin-induced injury in MCK(m)-hLPL mice. Similarly, an almost complete loss of myogenic potential was observed in C2C12 murine myoblasts upon overexpression of LPL. Our findings directly link lipid overload to muscle damage, impaired regeneration and loss of performance. These findings support the concept of lipotoxicity and are a further step to explain pathological effects seen in muscle of obese patients, patients with the metabolic syndrome and patients with cancer-associated cachexia.
authors: Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria.
authors: K P
authors: KP
authors: Tamilarasan
authors: H
authors: H
authors: Temmel
authors: S K
authors: SK
authors: Das
authors: W
authors: W
authors: Al Zoughbi
authors: S
authors: S
authors: Schauer
authors: P W
authors: PW
authors: Vesely
authors: G
authors: G
authors: Hoefler
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D012038:Regeneration; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D014280:Triglycerides; D003402:Creatine Kinase; D008071:Lipoprotein Lipase