Resveratrol Blunts Mitochondrial Loss in Slow and Mixed Skeletal Muscle Phenotypes of Non-Human Primates following a Long-Term High Fat/Sugar Diet

Abstract

Mitochondrial biogenesis and destruction in skeletal muscle are coordinated by distinct signaling pathways that are influenced by internal and exogenous variables including, but not limited to, muscle phenotype, physical activity, dietary composition, or drug administration. Previously we found that long-term resveratrol administration (up to 480 mg/day) ameliorates the slow-to-fast phenotypic shift in soleus muscles and promotes the expression in slow myosin heavy chain in the mixed plantaris muscle of non-human primates consuming a high fat/sugar (HFS) diet. Here, we expand on these earlier findings by examining whether mitochondrial content and the markers that dictate their biogenesis and mitophagy/autophagy are similarly affected by HFS and/or influenced by resveratrol while consuming this diet (HFSR). Compared to controls (n = 9), there was a ∼20–25% decrease in mitochondrial content in HFS (n = 8) muscles as reflected in the COX2- and CYTB-to-GAPDH ratios using PCR analysis, which was blunted by resveratrol in HFSR (n = 7) soleus and, to a lesser degree, in plantaris muscles. A ∼1.5 and 3-fold increase in Rev-erb-α protein was detected in HFSR soleus and plantaris muscles compared to controls, respectively. Unlike in HFSR animals, HFS soleus and plantaris muscles exhibited a ∼2-fold elevation in phosphor-AMPKα (Thr172). HFS soleus muscles had elevated phosphorylated-to-total TANK binding protein-1 (TBK1) ratio suggesting an enhancement in mito/autophagic events. Taken together, resveratrol appears to blunt mitochondrial losses with a high fat/sugar diet by tempering mito/autophagy rather than promoting mitochondrial biogenesis, suggesting that the quantity of daily resveratrol supplement ingested and/or its long-term consumption are important considerations.

Supplemental data for this article is available online at http://dx.doi.org/ .

Keywords:

• Biogenesis
• mitophagy
• Rev-erb-α
• TBK1

Acknowledgements

The authors would like to thank Mr. Beau Pullman for technical expertise and insightful discussions.

Disclosure statement

The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Funding

This study was supported, in part, by the Intramural Research Program, National Institute on Aging, NIH.

Authors’ contribution

JPKH: theory/design, data collection/interpretation/preparation; JAM: theory/design; RC: theory/design. All authors contributed to either the drafting or revising the manuscript at different stages and all have approved the final version.

Additional information

Notes on contributors

Jon-Philippe K. Hyatt

JP Hyatt, is an Associate Professor at in the College of Integrative Sciences and Arts at Arizona State University. Dr. Hyatt earned his Ph.D. in 2002 from UCLA in Molecular, Cellular, and Integrative Physiology specializing in skeletal muscle plasticity. In 2004, he started teaching and researching with undergraduate students at Georgetown University in the Human Science department until 2016 when he moved to his current position. At ASU, Dr. Hyatt teaches courses in anatomy and physiology and maintains a research laboratory examining skeletal muscle adaptation to exercise and nutrition.

Rafael de Cabo

Rafael de Cabo, earned his Ph.D. in 2000 from the Department of Foods and Nutrition at Purdue University. Upon completion of his graduate education, he received a postdoctoral position in the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, Maryland. In 2004, he was appointed as a tenure track investigator in the Laboratory of Experimental Gerontology. He is now a senior investigator and Chief of the Translational Gerontology Branch at NIA. He is the author or coauthor of 345 publications. Dr de Cabo is Deputy Editor in Chief, Journal of Gerontology Biological Sciences and serves on the editorial boards of Aging Cell, BBA-Molecular Mechanisms of Disease, Aging Research Reviews, Longevity & Healthspan, Impact Aging, AGE and is one of the founding editors of Microbial Cell.

Julie A. Mattison

Julie Mattison, is a Staff Scientist/Facility Head for a Nonhuman Primate Core program at the National Institute on Aging Intramural Research Program. The Core has been fundamental in supporting multi-disciplinary translational aging projects and an extensive tissue bank. Dr. Mattison earned her Ph.D. in 2000 from the Physiology Department at Southern Illinois University. She joined the NIA as a post-doctoral fellow and was appointed as a Staff Scientist in 2006. She has coauthored more than 100 publications including seminal papers on calorie restriction in nonhuman primates.