Vitamin D was initially identified as the cure for rickets. Its metabolism and its action on bone and growth plate are now well recognized. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D) probably has, however, a much wider spectrum of activities because the vitamin D receptor (VDR) is expressed in virtually all nucleated cells, the activating CYP27B1 or 1 -hydroxylase is expressed in at least 10 different tissues outside the kidney, and a very large number of genes (maybe even 3% of the whole mouse or human genome) are directly or indirectly regulated by this hormone (1–3). This should not be a surprise because most ligands for nuclear receptors, such as estrogens or androgens, glucocorticoids, or peroxisome proliferator-activated receptor ligands, also regulate a large number of genes and modify cell fate in many tissues. The muscle is a special potential target for the vitamin D endocrine system. Severe myopathy is well recognized as a major consequence of severe rickets, as already described in the 17th century, and is still a potential problem in patients with severe vitamin D deficiency due to chronic renal failure or in patients with a genetic deficiency of CYP27B1 (pseudovitamin D deficiency). This myopathy can be rapidly and impressively corrected by the appropriate vitamin D therapy (2). Sinha et al (4) report in this issue of the JCEM a beneficial effect of vitamin D supplementation of severely deficient but otherwise healthy adults on muscle weakness, and they explain this by improved mitochondrial function as measured in vivo using 31-phosphate nuclear magnetic resonance (NMR) spectroscopy . Phospho-creatinine (Pcreatinine) is an important storage mechanism of energy in muscle to satisfy rapid and extensive energy needs during exercise. Three parameters, muscle content of inorganic phosphate, P-creatinine, and the ratio of P-creatinine over inorganic phosphate, were measured in vivo with stateof-the-art technology. All parameters did not differ between vitamin D-deficient subjects and controls and did not change after vitamin D supplementation. The time needed to recover P-creatinine stores after exercise (and the disappearance rate of the substrate ADP), a parameter of efficacy of ATP production and thus of oxidative function of mitochondria, however, was markedly better/ shorter after vitamin D repletion and correlated with serum 25-hydroxyvitamin D (25OHD) concentrations. These data indicate that the energy production during the recovery phase of modest exercise by muscle mitochondria is impaired in subjects with severe vitamin D deficiency. This situation is likely to be persistent throughout rest and exercise, but this would be hard to measure in vivo because of technical reasons. Such slower energy generation in skeletal muscle mitochondria could likely contribute to decreased muscle strength and a rapid feeling of fatigue during moderate exercise. There are, however, several limitations in this nonrandomized study because the number of subjects is small, only a single dose (20 000 IU of vitamin D3 every other day for 12 wk) was used, and the control subjects were not fully vitamin D replete (mean serum 25OHD, 18 ng/ml) and were not studied again after similar vitamin D supplementation. Moreover, the halflife of recovery of P-creatinine after vitamin D supplementation was greater in the supplemented group than in the baseline control group, but this may in fact be due to their nonoptimal vitamin D status. Finally, a more direct comparison between changes in energy recovery and muscle function or fatigue sensation is needed. The mitochondrial dysfunction could be due to a wide variety of reasons such as decreased vascular or oxygen supply (unlikely), decreased mitochondrial number (not observed in vitamin D-deficient animal muscle), or deficient enzyme function of the oxidative pathway (eg, by direct effect of the vitamin