Differences in Mitochondrial Coupling Reveal a Novel Signature of Mitohormesis in Muscle of Healthy Individuals.

Abstract

CONTEXT:

Reduced mitochondrial coupling (ATP/O2 [P/O]) is associated with sedentariness and insulin resistance. Interpreting the physiological relevance of P/O measured in vitro is challenging.

OBJECTIVE:

To evaluate muscle mitochondrial function and associated transcriptional profiles in nonobese healthy individuals distinguished by their in vivo P/O.

DESIGN:

Individuals from an ancillary study of Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy phase 2 were assessed at baseline.

SETTING:

The study was performed at Pennington Biomedical Research Center.

PARTICIPANTS:

Forty-seven (18 males, 26-50 y of age) sedentary, healthy nonobese individuals were divided into 2 groups based on their in vivo P/O.

INTERVENTION:

None. Main Outcome(s): Body composition by dual-energy x-ray absorptiometry, in vivo mitochondrial function (P/O and maximal ATP synthetic capacity) by 31P-magnetic resonance spectroscopy and optical spectroscopy were measured. A muscle biopsy was performed to measure fiber type, transcriptional profiling (microarray), and protein expressions.

RESULTS:

No differences in body composition, peak aerobic capacity, type I fiber content, or mitochondrial DNA copy number were observed between the 2 groups. Compared with the uncoupled group (lower P/O), the coupled group (higher P/O) had higher rates of maximal ATP synthetic capacity (maximal ATP synthetic capacity, P < .01). Transcriptomics analyses revealed higher expressions of genes involved in mitochondrial remodeling and the oxidative stress response in the coupled group. A trend for higher mitonuclear protein imbalance (P = .06) and an elevated mitochondrial unfolded protein response (heat shock protein 60 protein; P = .004) were also identified in the coupled group.

CONCLUSIONS:

Higher muscle mitochondrial coupling is accompanied by an overall elevation in mitochondrial function, a novel transcriptional signature of oxidative stress and mitochondrial remodeling and indications of an mitochondrial unfolded protein response.

• Authors: Lauren M Sparks, Leanne M Redman, Kevin E Conley, Mary-Ellen Harper, Andrew Hodges, Alexey Eroshkin, Sheila R Costford, Meghan E Gabriel, Fanchao Yi, Cherie Shook, Heather H Cornnell, Eric Ravussin, Steven R Smith
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 101 Issue 12 Pg. 4994-5003 (12 2016) ISSN: 1945-7197 [Electronic] United States
• PMID: 27710240 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• Adenosine Triphosphate

Topics

• Absorptiometry, Photon
• Adenosine Triphosphate (metabolism)
• Adult
• Female
• Gene Expression Profiling
• Hormesis
• Humans
• Magnetic Resonance Spectroscopy
• Male
• Middle Aged
• Mitochondria, Muscle (metabolism)
• Muscle, Skeletal (metabolism)
• Oxidative Coupling
• Oxidative Stress
• Oxygen Consumption
• Sedentary Behavior