In Vivo Mitochondrial ATP Production Is Improved in Older Adult Skeletal Muscle After a Single Dose of Elamipretide in a Randomized Trial

Abstract

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 (∆ATPmax; P=0.055, %∆ATPmax; 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.

Preventive effects of the butanol fraction of Justicia procumbens L. against dexamethasone-induced muscle atrophy in C2C12 myotubes

“…It also promotes skeletal muscle wasting and appears in various models of muscle atrophy, including disuse, diabetes, and aging [ 53 , 54 , 55 , 56 ]. It is well known that mitochondrial content and ATP production capacity play an important role in maintaining normal mitochondrial function and muscle function [ 57 , 58 ]. A previous study reported that DEX induces muscle atrophy by promoting mitochondrial dysfunction through decreased ATP production as well as reduced mitochondrial content in C2C12 myotubes compared to the native state [ 59 ].…”

Preservation of Mitochondrial Membrane Potential is Necessary for Lifespan Extension from Dietary Restriction

“…Developing tools to precisely control ATP/ADP levels in both the cytosol and in the mitochondrial matrix, as well as control over Δψ m , will be necessary first steps in elucidating more detail in experimental models. However, emerging evidence suggests that directly intervening on ANT function is possible to facilitate better understanding of mitochondrial energetics in vivo in the context of aging [18, 55]. Similarly, targeting IF1 in mammalian cells has been informative for probing the mechanisms of nutrient-sensing signaling and Δψ m [56, 57].…”

Intermittent treatment with elamipretide preserves exercise tolerance in aged female mice

“…This limitation makes it difficult to compare to other aging interventions such as those in the National Institute of Aging Intervention Testing Program (ITP). Recent evidence in older humans demonstrated that a single treatment with ELAM improved in vivo mitochondrial function immediately after treatment and returned to placebo level a week later ( 11 ). However, this study suggested that effects on skeletal muscle fatigue resistance were elevated a week after treatment.…”

“…Previous work has demonstrated that the mitochondrial-targeted peptide elamipretide (ELAM), previously referred to as Bendavia, MTP-131, and SS-31, is an effective intervention to reverse skeletal muscle ( 5, 6 ), cardiac ( 7 ), kidney ( 8 ), retina ( 9 ), and cognitive dysfunction in aged mice ( 10 ). Clinical trials in aged humans demonstrated improvements of in vivo mitochondrial energetics after a single treatment ( 11 ). This improvement was short-lived, consistent with the short half-life of the compound( 5 ).…”