Sarcopenia, presenting as loss of muscle mass and function, is a common and debilitating complication of endogenous or exogenous glucocorticoid excess, and a frequent symptom of chronic stress-related conditions, such as cancer, HIV, chronic renal or cardiac disease, and normal aging; yet to date, the underlying pathogenetic mechanisms remain unclear and targeted therapeutic interventions are limited. Mitochondria play a pivotal role in skeletal muscle energy homeostasis and calcium buffering, as well as radical oxygen species (ROS) generation, apoptosis and cell death. Steroid myopathy is associated with electron microscopic changes in skeletal muscle mitochondria, decreased enzymatic activity and mitochondrial DNA depletion. Moreover, increased production of ROS, namely hydrogen peroxide and superoxide, by dexamethasone, a synthetic glucocorticoid, contributes considerably to its adverse effects on skeletal myocytes, which can be prevented by antioxidant compounds (N-acetylcysteine, ascorbic acid) or enzymes (superoxide dismutase, catalase) in vitro. Beyond the well-described effects on fatty acid oxidation and energy metabolism, L-Carnitine (LCAR) exerts important anabolic and antioxidant-antiapoptotic effects. Acetyl-LCAR and lipoic acid have been shown to prevent mitochondria from oxidative decay and dysfunction, thereby preventing age-associated neurodegenerative symptoms, such as memory loss, and delaying the aging process. Acetyl LCAR administration to HIV patients increases serum IGF-I concentrations, suggesting anabolic effects, while selective trophic effects on skeletal muscular fibers in hemodialysis patients have also been demonstrated. Moreover, pretreatment with LCAR prevents doxorubicin-induced apoptosis of cardiomyocytes, by inhibiting the sphingomyelin hydrolysis and ceramide generation. To identify pathways involved in glucocorticoid- or stress-induced mitochondrial dysfunction in skeletal muscle we investigated the transcriptional adaptations that follow exposure of primary human skeletal myocytes to dexamethasone by screening 501 mitochondria-related genes with a custom-made human cDNA microarray chip (hMitChip, NICHD). In comparison, similar studies were performed with carnitine, to explore its role as anabolic/antiapoptotic agent in myocytes at the transcriptional level.
|Alesci, S; Manoli, I; Michopoulos, V J et al. (2006) Development of a human mitochondria-focused cDNA microarray (hMitChip) and validation in skeletal muscle cells: implications for pharmaco- and mitogenomics. Pharmacogenomics J 6:333-42|
|Manoli, Irini; Le, Hanh; Alesci, Salvatore et al. (2005) Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells. FASEB J 19:1359-61|
|Ilias, Ioannis; Manoli, Irini; Blackman, Marc R et al. (2004) L-Carnitine and acetyl-L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy. Mitochondrion 4:163-8|