Compensation for mitochondrial dysfunction preserves energy homeostasis in muscle of individuals with pre-manifest HD
Huntington Disease is a genetic disorder that manifests brain atrophy and loss of neural cell metabolites well before the onset of clinical symptoms. Here we show using new non-invasive tools profound mitochondrial changes in muscle that trade-off to maintain cell energy homeostasis in pre-manifest individuals as compared to age and gender matched controls. Innovative optical and magnetic resonance spectroscopic methods for measuring ATP synthesis and O2 uptake in vivo revealed a reduction in mitochondrial coupling (ATP/O2) in proportion to early motor dysfunction as measured by the Unified Huntington’s Disease Rating Score (UHDRS). They also revealed unchanged mitochondrial phosphorylation capacity (ATPmax) and stable levels of energetic metabolites (PCr and ATP). This stability of energy state and ATPmax is consistent with oxidative stress not only causing mitochondrial uncoupling but also compensatory mitochondrial biogenesis. In contrast, atrophy of the caudate and loss of brain metabolites (NAA and Glutamine) per caudate volume in proportion to the UHDRS was apparent in these individuals. These results reveal that mutant huntingtin has a profound impact on both brain and muscle tissue well before the onset of clinical symptoms. They also show that the muscle compensates for this impact to maintain mitochondrial capacity, energy homeostasis and cell metabolite levels while atrophy and depletion of metabolites proceeds in the brain. This compensation for the impact of mutant huntington in muscle may hold the key to effective interventions for halting progression of this chronic disease in brain.