In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial.

BACKGROUND: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. RESULTS: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. CONCLUSIONS: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney disease.

The maintenance of functional independence is the top priority of patients with chronic kidney disease (CKD). Defects in mitochondrial energetics may compromise physical performance and independence. We investigated associations of the presence and severity of kidney disease with in vivo muscle energetics and the association of muscle energetics with physical performance. We performed measures of in vivo leg and hand muscle mitochondrial capacity (ATPmax) and resting ATP turnover (ATPflux) using 31phosphorus magnetic resonance spectroscopy and oxygen uptake (O2 uptake) by optical spectroscopy in 77 people (53 participants with CKD and 24 controls). We measured physical performance using the 6-minute walk test. Participants with CKD had a median estimated glomerular filtration rate (eGFR) of 33 ml/min per 1.73 m2. Participants with CKD had a -0.19 mM/s lower leg ATPmax compared with controls but no difference in hand ATPmax. Resting O2 uptake was higher in CKD compared with controls, despite no difference in ATPflux. ATPmax correlated with eGFR and serum bicarbonate among participants with GFR <60. ATPmax of the hand and leg correlated with 6-minute walking distance. The presence and severity of CKD associate with muscle mitochondrial capacity. Dysfunction of muscle mitochondrial energetics may contribute to reduced physical performance in CKD.

Building strength, endurance, and mobility using an astaxanthin formulation with functional training in elderly.

BACKGROUND: Building both strength and endurance has been a challenge in exercise training in the elderly, but dietary supplements hold promise as agents for improving muscle adaptation. Here, we test a formulation of natural products (AX: astaxanthin, 12 mg and tocotrienol, 10 mg and zinc, 6 mg) with both anti-inflammatory and antioxidant properties in combination with exercise. We conducted a randomized, double-blind, placebo-controlled study of elderly subjects (65-82 years) on a daily oral dose with interval walking exercise on an incline treadmill. METHODS: Forty-two subjects were fed AX or placebo for 4 months and trained 3 months (3×/week for 40-60 min) with increasing intervals of incline walking. Strength was measured as maximal voluntary force (MVC) in ankle dorsiflexion exercise, and tibialis anterior muscle size (cross-sectional area, CSA) was determined from magnetic resonance imaging. RESULTS: Greater endurance (exercise time in incline walking, >50%) and distance in 6 min walk (>8%) accompanied training in both treatments. Increases in MVC by 14.4% (±6.2%, mean ± SEM, P < 0.02, paired t-test), CSA by 2.7% (±1.0%, P < 0.01), and specific force by 11.6% (MVC/CSA, ±6.0%, P = 0.05) were found with AX treatment, but no change was evident in these properties with placebo treatment (MVC, 2.9% ± 5.6%; CSA, 0.6% ± 1.2%; MVC/CSA, 2.4 ± 5.7%; P > 0.6 for all). CONCLUSIONS: The AX formulation improved muscle strength and CSA in healthy elderly in addition to the elevation in endurance and walking distance found with exercise training alone. Thus, the AX formulation in combination with a functional training programme uniquely improved muscle strength, endurance, and mobility in the elderly.

Mitochondrial NAD(P)H In vivo: Identifying Natural Indicators of Oxidative Phosphorylation in the (31)P Magnetic Resonance Spectrum.

Natural indicators provide intrinsic probes of metabolism, biogenesis and oxidative protection. Nicotinamide adenine dinucleotide metabolites (NAD(P)) are one class of indicators that have roles as co-factors in oxidative phosphorylation, glycolysis, and anti-oxidant protection, as well as signaling in the mitochondrial biogenesis pathway. These many roles are made possible by the distinct redox states (NAD(P)(+) and NAD(P)H), which are compartmentalized between cytosol and mitochondria. Here we provide evidence for detection of NAD(P)(+) and NAD(P)H in separate mitochondrial and cytosol pools in vivo in human tissue by phosphorus magnetic resonance spectroscopy ((31)P MRS). These NAD(P) pools are identified by chemical standards (NAD(+), NADP(+), and NADH) and by physiological tests. A unique resonance reflecting mitochondrial NAD(P)H is revealed by the changes elicited by elevation of mitochondrial oxidation. The decline of NAD(P)H with oxidation is matched by a stoichiometric rise in the NAD(P)(+) peak. This unique resonance also provides a measure of the improvement in mitochondrial oxidation that parallels the greater phosphorylation found after exercise training in these elderly subjects. The implication is that the dynamics of the mitochondrial NAD(P)H peak provides an intrinsic probe of the reversal of mitochondrial dysfunction in elderly muscle. Thus, non-invasive detection of NAD(P)(+) and NAD(P)H in cytosol vs. mitochondria yields natural indicators of redox compartmentalization and sensitive intrinsic probes of the improvement of mitochondrial function with an intervention in human tissues in vivo. These natural indicators hold the promise of providing mechanistic insight into metabolism and mitochondrial function in vivo in a range of tissues in health, disease and with treatment.