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.

High-fat feeding does not induce an autophagic or apoptotic phenotype in female rat skeletal muscle

“…It is important to note that this study was performed in female rats, while similar work has used male rodents 10,11 or has not specified the gender. 5,12 Thus, discrepancies between our work and previous literature may be a result of gender-related differences. In fact, a number of physiological and metabolic effects of a HF diet have been shown to be sex-dimorphic.…”

“…49 However, we did not observe changes in muscle weight or fiber CSA. Although muscle cell culture experiments 7,8 and transgenic animals with extreme muscle lipid overload 5 demonstrate signs of elevated apoptosis such as DNA fragmentation, few apoptotic differences are observed in obese Zucker rats 12 as well as ob/ob and HF-fed mice. 10 Thus, this raises the likelihood that under most physiological and pathological ''high-fat'' conditions, skeletal muscle is generally capable of mitigating apoptosis.…”

“…5 In vitro studies have demonstrated that exposure of myotubes to a high-fat (HF) environment results in increased caspase-3 activity 6 and DNA fragmentation. [7][8][9] Similarly, MCK(m)-hLPL mice (which accumulate muscle lipids) have a higher percentage of apoptotic nuclei in muscle, 5 while triacylglycerol infusion into lean mice increases muscle caspase-3 activation. 10 Additionally, 16 weeks of HF feeding has been shown to increase caspase-3 activity in mouse muscle.…”

Diabetic mice exhibited a peculiar alteration in body composition with exaggerated ectopic fat deposition after muscle injury due to anomalous cell differentiation

“…IMF accumulation in obese patients is positively correlated with insulin resistance and reduced muscle performance . Lipid overload causes impaired skeletal muscle function because of a reduction of muscle mass and ultrastructural damage; therefore, lipotoxic species induced via IMF deposition also interfere with insulin signalling and muscle repair. Moreover, muscle regenerative capacity declines with ageing .…”

Monocarboxylate transporter expression at the onset of skeletal muscle regeneration

“…; Tamilarasan et al. ). Damage to skeletal muscle is associated with myofiber disruption which induces a local inflammatory response and increased circulating creatine kinase levels (McClung et al.…”