Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo

Abstract

Faster aging is predicted in more active tissues and animals because of greater reactive oxygen species generation. Yet age-related cell loss is greater in less active cell types, such as type II muscle fibers. Mitochondrial uncoupling has been proposed as a mechanism that reduces reactive oxygen species production and could account for this paradox between longevity and activity. We distinguished these hypotheses by using innovative optical and magnetic resonance spectroscopic methods applied to noninvasively measured ATP synthesis and O(2) uptake in vivo in human muscle. Here we show that mitochondrial function is unchanged with age in mildly uncoupled tibialis anterior muscle (75% type I) despite a high respiratory rate in adults. In contrast, substantial uncoupling and loss of cellular [ATP] indicative of mitochondrial dysfunction with age was found in the lower respiring and well coupled first dorsal interosseus (43-50% type II) of the same subjects. These results reject respiration rate as the sole factor impacting the tempo of cellular aging. Instead, they support mild uncoupling as a mechanism protecting mitochondrial function and contributing to the paradoxical longevity of the most active muscle fibers.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Spectroscopic measurements during ischemia that yield O2 uptake, ATP flux, and energy coupling (P/O) in an adult human TA muscle at rest. (Upper) An optical spectroscopic measurement distinguishing Mb and Hb O2 saturation that is used with their respective in vivo concentrations (Table 1) to determine O2 uptake during the initial period of ischemia. (Lower) MRS measurement of the dynamics of [PCr]. The [PCr] breakdown during ischemia measures ATP turnover by the cell that must be met by ATP supply from the mitochondria under aerobic conditions.

Fig. 2.

Energy fluxes used to determine mitochondrial coupling in FDI and TA muscles of adult and elderly subjects. (a) Oxygen uptake rates. (b) Oxidative phosphorylation rates (ATP flux). (c) Coupling of oxidation to phosphorylation (P/O). +, significant difference between adult TA and adult FDI; ∗, significant difference between adult and elderly values of each muscle.

Fig. 3.

Mitochondrial changes with age measured as depletion of [ATP] (Δ[ATP]/[PCr]) versus energy uncoupling (ΔP/O) in TA and FDI (this study), vastus lateralis (VL) (15), and mouse hindlimb muscles (MH) (12).

Fig. 4.

Uncoupling of muscle in elderly human muscles as a function of percent type II fiber content [soleus (SOL) (22), TA and FDI (this study), and vastus lateralis (VL) (15); muscle fiber type content is from Johnson et al. (50)]. Relative uncoupling with age is determined by normalizing the elderly coupling value to the adult value to permit the comparison studies using different methodologies.