# ATP and NAD+
## 4 Discussion  
Mitochondrial defects associated with parkinson can be the result of genetic variants or environmental and metabolic insults [5; 40]. Despite interest in the role of mitochondrial dysfunction in the etiology of PD, few studies have examined the presence of mitochondrial defects in peripheral tissues. We take advantage of the ability to use \({}^{31}\)P MRS to non-invasively interrogate mitochondrial function in skeletal muscle to test whether PD is associated with mitochondrial dysfunction and metabolic disruption in peripheral tissues. We identified significant mitochondrial dysfunction in the TA muscle compared to a historical dataset from healthy age-matched controls. Deeper analysis of the resting MRS spectra also indicated disruption of NAD metabolism in the PD subjects. These metabolic defects were associated with poor skeletal muscle function in both the hand and leg muscles, suggesting these cellular changes may be clinically relevant. Figure 4: Muscle function in leg (TA) and hand (FDI). Comparison of muscle function between control and subjects with [PERSON]’s disease. Muscle specific force in the (**A**) TA and (**C**) FDI; Muscle endurance measured as number of voluntary muscle contractions in the (**B**) TA and (**D**) FDI. *\(p<0.05\), **\(p<0.01\), ***\(p<0.0001\). To test whether PD is associated with systemic mitochondrial dysfunction we used \({}^{31}\)P MRS to measure in vivo ATPmax in hand and leg skeletal muscles. Several studies have demonstrated that in vivo ATPmax is associated with poor physical function with age, although there is a lot of variation in mitochondrial function in older adults [18; 19; 41]. To test whether PD is associated with skeletal muscle mitochondrial dysfunction independent of age, we compared in vivo ATPmax in hand and leg from 30 newly recruited PD subjects with a dataset of healthy control subjects collected as part of the screening process for previous studies at the Translational Bioenergetics Laboratory. In vivo ATPmax provides a direct estimate of the capacity for mitochondrial ATP production under physiological conditions in the skeletal muscle. The significantly lower ATPmax in the TA in the PD subjects indicates that, although the primary functional defects in PD are believed to originate from the CNS, the mitochondrial dysfunction extends to peripheral tissues. The absence of a difference between healthy controls and PD subjects in ATPmax in the hand indicates that the extent of mitochondrial dysfunction, while not confined to the CNS, appears to vary among tissues. Although ATPmax provides a measure of mitochondrial capacity, it does not provide much insight into the effect of PD on resting metabolism or metabolic homeostasis. To address this question, we attempted to measure nicotinamide levels from the \({}^{31}\)P spectra. NAD metabolism has received a lot of attention due to its multiple roles in sirtuin-based deacetylation and PARP DNA damage and repair pathways [42]. In addition, NADH, the reduced form of NAD, is generated by the tricarboxylic acid cycle in the matrix of the mitochondria and provides the main electron input into complex I of the ETS to initiate oxidative phosphorylation. Disrupted NAD and NADH levels are associated with defective complex I function [43; 44] and multiple chronic disease conditions, including Parkinson's disease and Alzheimer's disease models [45]. Most previous studies focused on nicotinamide have measured metabolite levels ex vivo in blood from human subjects or tissue biopsies in animal models. However, these metabolites are represented by small peaks on the shoulder of the alpha-ATP peak in the \({}^{31}\)P spectra and thus can be assessed in vivo in brain and skeletal muscles [38; 46]. In the current study, we were able to quantify NAD from spectra from the leg muscles only due to the lower signal quality coming from the smaller FDI muscles of the hand.