Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.

The effects of neuromuscular electrical stimulation to the ankle pronators on neural excitability & functional status in patients with chronic ankle instability.

OBJECTIVES: Chronic ankle instability (CAI) is associated with decreased neural excitability that negatively impacts function. This study assessed a 2-week neuromuscular electrical stimulation (NMES) or transcutaneous electrical nerve stimulation (TENS) intervention over the ankle pronators on neural excitability, performance, and patient-reported function in patients with CAI. STUDY DESIGN: Randomized controlled trial. PARTICIPANTS: Twenty participants with CAI completed the study. MAIN OUTCOME MEASURES: Participants were assessed for reflexive and corticospinal excitability to the ankle muscles, dynamic balance, side-hop test performance and patient-reported outcomes at baseline, post-intervention (2-weeks), and retention (4-weeks). Between baseline and post-intervention, participants reported for 5 sessions where they received either sub-noxious NMES (n = 11) or sensory-level TENS (n = 9) over the ankle pronators. RESULTS: Improved reflexive excitability to the ankle pronators was observed in TENS at post-intervention (p = 0.030) and retention (p = 0.029). Cortical excitability to the dorsiflexors increased in TENS at post-intervention (p = 0.017), but not at retention (p = 0.511). No significant changes were found for other neural measures, balance ability, hopping, or patient-reported function (p > 0.050). CONCLUSIONS: Our results suggest TENS modified neural excitability; however, these changes were not enough to impact clinical function. While TENS may be capable of neuromodulation, it may require rehabilitative exercise to generate lasting changes. NCT04322409. LEVEL OF EVIDENCE: Level 2.