MicroRNAs emerge as modulators of NAD+-dependent energy metabolism in skeletal muscle.

Obesity, type 2 diabetes, and related metabolic disorders are associated with reduced mitochondrial function in skeletal muscle and other organs (1). However, causality of aberrant mitochondrial activity in the etiology of these diseases and the exact mechanism(s) linking metabolic pathologies to mitochondrial dysfunction are still under debate. Therefore, a better molecular understanding of this observation is required in order to design novel therapeutic strategies aimed at modulation of mitochondrial function in these disease contexts. The silent mating type information regulation 2 homolog 1 (SIRT-1) and the peroxisome proliferator-activated receptor g coactivators 1 (PGC-1) are important regulators of mitochondrial function in skeletal muscle (1). In response to deacetylation by SIRT-1, PGC-1a is activated and subsequently promotes an oxidative muscle fiber phenotype. In turn, SIRT-1 activity is regulated by the substrate NAD, and thus acts as an intracellular rheostat by increasing mitochondrial biogenesis to match the energy needs of the cell (2). Interestingly, recent studies have exploited this mechanism by using the NAD precursors nicotinamide riboside (3) and nicotinamide mononucleotide (4) to increase SIRT1 activity and thereby the oxidative capacity of skeletal muscle. Alternatively, intracellular NAD can be elevated through inhibition of other enzymes that use NAD. In particular, the poly(ADP-ribose) polymerases (PARPs), which metabolize NAD to form polymers of ADP-ribose (PAR) on other proteins, are major consumers of NAD in various cell types. PARPs are involved in regulation of several distinct cellular processes, such as DNA repair, inflammation, and differentiation (5), but they have also recently been recognized as having important roles in metabolism (6). In fact, germ-line deletion of either PARP-1 or PARP-2, or pharmacological inhibition of PARP activity by PJ-34, results in elevated intracellular NAD levels in skeletal muscle with the expected outcome of increased SIRT-1 activity and mitochondrial oxidative function (7,8). In most tissues, PARP-1 accounts for the vast majority (.85%) of cellular PARP activity, and is therefore also the major NAD consumer (6). Thus, PARP-1 deletion presumably affects SIRT-1 primarily due to increased NAD levels (8). In contrast, even though PARP-2 null mice also show increased NAD levels (7), PARP-2 also acts as a transcriptional repressor of SIRT-1 (7). Modulation of PARP activity provides a novel therapeutic strategy to increase SIRT-1 expression and activity in skeletal muscle, and represents an alternative to pharmacological activation of SIRT-1 using resveratrol or SRT1720 (9,10). Interestingly, several studies indicate that PARP activity inmurine skeletalmuscle is dysregulated during high-fat diet (HFD) feeding (8) and aging (11), implying a direct involvement of PARPs in development of metabolic dysfunction in muscle. This idea is now further supported in the study by Mohamed et al. (12) published in this issue, in which the authors demonstrate that skeletal muscle PARylation was increased in HFD-fed mice concomitant with elevated expression of PARP-2. Surprisingly, in contrast to other studies that have reported elevated PARP-1 in HFD-fed mice (8), the authors detected no differences in PARP-1 expression with HFD feeding. As expected however, elevated PARP-2 expression was associated with lower NAD levels and reduced SIRT-1 expression, together with a reduction in mitochondrial oxidative function. Depletion of intracellular NAD through increased PARP-2 activity was therefore postulated as a major mechanism leading to mitochondrial dysfunction in these mice. Although simple and attractive, the findings do not exclude the idea that PARPs, apart from acting as a transcriptional repressor of SIRT-1 (7), also interact with