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Recent evidence supports that TNF-[alpha], long considered a catabolic factor, may also have a physiological function in skeletal muscle. The catabolic view, mainly based on correlative studies in human and in vivo animal models, was challenged by experiments with myoblasts, in which TNF-[alpha] induced differentiation. The biological effects of TNF-[alpha] in differentiated muscle, however, remain poorly understood. In the present study, we tested whether TNF-[alpha] has growth-promoting effects in myotubes, and we characterized the mechanisms leading to these effects. Treatment of [C.sub.2][C.sub.12] myotubes with TNF-[alpha] for 24 h increased protein synthesis (PS) and enhanced cellular dehydrogenase activity by 22 and 26%, respectively, without changing cell numbers. These effects were confirmed in myotubes differentiated from primary rat myoblasts. TNF-[alpha] activated two signaling cascades: 1) ERK1/2 and its target eIF4E and 2) Akt and its downstream effectors GSK-3, [p70.sup.S6K], and 4E-BP1. TNF-[alpha]-induced phosphorylation of Akt, and ERK1/2 was inhibited by an antibody against TNF-[alpha] receptor 1 (TNF-R1). PD-98059 pretreatment abolished TNF-[alpha]-induced phosphorylation of ERK1/2 and eIF4E, whereas PS was only partially inhibited. LY-294002 completely abolished TNF-[alpha]-induced stimulation of PS as well as phosphorylation of Akt and its downstream targets GSK-3, [p70.sup.S6K], and 4E-BP1. Rapamycin inhibited TNF-[alpha]-induced phosphorylation of the roTOR C1 target [p70.sup.S6K] without altering TNF-[alpha]-induced PS and 4E-BP1 phosphorylation. In conclusion, our results provide evidence that TNF-[alpha] enhances PS in myotubes and that this is based on enhanced protein translation mediated by the TNF-R1 and PI3K-Akt and MEK-ERK signaling cascades. tumor necrosis factor-[alpha]; tumor necrosis factor-[alpha] receptor 1; phosphatidylinositol 3-kinase; mitogen-activated protein kinase/extracellular signal-related kinase

Aging is associated with a decline in cardiac function due to a decreased myocardial reserve. This adverse cardiac remodeling comprises of a variety of changes, including a reduction in mitochondrial function and a decline in the expression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a central regulator of mitochondrial biogenesis and metabolic adaptation in the myocardium. To study the etiological involvement of PGC-1α in cardiac aging, we used mouse models mimicking the modest down- and upregulation of this coactivator in the old and the exercised heart, respectively. Youngmice with reduced cardiac expression of PGC-1α recapitulated part of the age-related impairment in mitochondrial gene expression, but otherwise did not aggravate the aging process. Inversely however, moderate overexpression of PGC-1α counteracts numerous key age-related remodeling changes, e.g., by improving blood pressure, age-associated apoptosis, and collagen accumulation, as well as in the expression of many, but not all cardiac genes involved in mitochondrial biogenesis, dynamics, metabolism, calcium handling and contractility. Thus, while the reduction of PGC-1α in the heart is insufficient to cause an aging phenotype, moderate overexpression reduces pathological remodeling of older hearts and could thereby contribute to the beneficial effects of exercise on cardiac function in aging. [ABSTRACT FROM AUTHOR]