Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 3; pp. 1057 - 1062
• Main Authors: Amara, Catherine E, Shankland, Eric G, Jubrias, Sharon A, Marcinek, David J, Kushmerick, Martin J, Conley, Kevin E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.01.2007; National Acad Sciences
• Subjects: adenosine triphosphate; Adenosine Triphosphate - metabolism; Adult; Adults; Age; Aging; ATP; Biological Sciences; Cellular biology; Cellular senescence; Cellular Senescence - physiology; Female; Humans; Ischemia; Longevity; Male; Middle Aged; Mitochondria; Mitochondria, Muscle - metabolism; muscle fibers; Muscles; Muscular system; NMR; Nuclear magnetic resonance; Older adults; oxygen; Oxygen - metabolism; Phosphates - metabolism; Reactive oxygen species; Respiration; respiratory rate; Spectroscopy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0610131104

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 O₂ 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.