Congratulations Taylor Valentino, PhD
On Thursday, January 20, 2022 Taylor Valentino successfully defended his dissertation and earned his doctoral degree. Congratulations, Dr. Valentino!
REGULATION OF SKELETAL MUSCLE PLASTICITY BY THE GUT MICROBIOME
Doctoral Committee
Dr. John McCarthy, Department of Physiology, Mentor
Dr. Mariana Nikolova-Karakashian, Department of Physiology
Dr. Lance Johnson, Department of Physiology
Dr. Michael Flythe, Equine Programs
Dr. Steve Estus, Department of Physiology
Dr. Eric Blalock, Pharmacology & Nutritional Sciences, Outside Examiner
Abstract
Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaption to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight and mean and fiber-type specific cross-sectional area (CSA). The plantaris muscle of mice who ran with antibiotic-induced dysbiosis showed a blunted glycolytic to oxidative fiber-type shift, myonuclear accretion and satellite cell abundance compared to non-treated runners. These results are the first to demonstrate that an intact microbiome is necessary for skeletal muscle adaption to exercise.
I next wanted to test if the gut microbiome mitigates skeletal muscle atrophy induced by hind limb immobilization. Eighteen, four-month old, female C57Bl/6J mice were divided into two groups (n=9/group), that received cecal microbial transfers from either exercise-trained or sedentary donors. After four weeks of cecal transplants, the recipient mice underwent 10-days of single leg hind-limb immobilization. Immunohistochemistry analysis revealed that the recipients of the exercise-trained donors experienced significantly less skeletal muscle atrophy of the soleus muscle, as measures by mean fiber and fiber-type specific CSA. The transfer of microbiome from exercise-trained donors also led to a preservation of Type-2A fibers in the immobilized soleus muscle. These results demonstrated that the transfer of a microbiome from an exercise-trained host into recipients mitigated skeletal muscle atrophy, in addition to the persevering Type-2A fibers abundance during atrophy
In an effort to better understand how the gut microbiome acts to modulate skeletal muscle mass and fiber-type composition, metagenomic sequencing was performed on donor and recipient of exercise-trained and sedentary cecal content. Sequencing data revealed significant differences in the microbiome between the two recipient groups. Further microbial functional comparisons were made and distinguished significant associations in fucose degradation and histidine metabolism in the recipients who received microbiome from exercised-trained donors. To further interrogate the metagenomic sequencing, microbial sequence features were analyzed with MelonnPan to determine predictive metabolites associated with each recipient group. Metabolites related to lipids and bile acids were significantly associated with the recipients of the exercise-trained donors. There was a trend for imidazole propionate to be associated with the recipients of the exercise-trained donors. The metagenomic analysis indicated the microbiome from an exercise-trained host was associated with metabolic pathways that generate short chain fatty acids (fucose degradation) and the histidine-derived metabolite imidazole propionate.
The results from this dissertation provide evidence of crosstalk between skeletal muscle and the gut microbiome, providing for the first-time data that demonstrating the gut microbiome influences both anabolic and catabolic signaling in skeletal muscle. Although a direct mechanism for the skeletal muscle-gut microbiome interaction, metabolites (short chain fatty acids and imidazole propionate) were identified as possible candidate for future study. A general conclusion from the two studies described in this dissertation provides new evidence for the regulation of skeletal muscle mass and fiber-type composition.
Future work will need to focus on the identification of the gut microbial-derived metabolites promote anabolic pathways in skeletal muscle. Additional studies should also determine if the attenuation in atrophy induced by hind limb immobilization is conserved in other models of atrophy as observed with skeletal muscle wasting diseases and space exploration.
Acknowledgements
The following dissertation, while an individual work, benefited from the insights and direction of several people. First, my Dissertation Chair, John McCarthy, his unbridled optimism, obsessive excitement for skeletal muscle hypotrophy and relentless dedication to his work was a constant source of inspiration. Our morning conversation will be imprinted in my memories and was always the best way to start the day. Next, I wish to thank the complete Dissertation Committee, and outside reader, respectively: Steve Estus PhD, Michael Flythe PhD, Lance Johnson PhD, Mariana Nikolova-Karakashian PhD and Eric Blalock PhD. Your additional guidance throughout my PhD has be paramount not only for my successful graduation but for my future aspirations. Committee meetings were never a moment of panic or fear, rather a cultivating environment where I got take part in belly of scientific logic and rationale. You are all extremely talented, intelligent and inspiring people. Dr. Blalock, thank you for taking th time to serve as my outside examiner.
In addition to the technical and instrumental assistance above, I received equally important assistance from family and friends. Current and formers members of the McCarthy lab and Center for Muscle Biology; Jensen Goh MS, Yuan Wen MD PhD, Alexander Alimov PhD, Ivan Vechetti PhD, Brooks Mobley PhD, Laura Brown PhD, Alex Keeble, Nick Thomas MS, Christine Lantham PhD, Camille Brightwell PhD, Chris Fry PhD, Kevin Murach PhD, Cory Dungan PhD, Kate Kosmac PhD and Charlotte Peterson PhD. You have all helped me tremendously in my time as a graduate student at UKY, THANK YOU!!!
My former mentors Marialice Kern PhD, C. Matthew Lee PhD and Maria Veri PhD. My love of science and exercise physiology began with your guidance, which you all enriched. I was able to complete goals I never thought I could because of your support and advising. Some of my most fondest memories are being with you all.
I receive invaluable help from administrative staff in the Physiology department- Tanya Graf and Andrew Hernandez. Thank you so very much for always being there for me. Ken Campbell PhD, you are a fantastic director of graduate studies and provided many hours of great conversation. Thank you for always clearing up my mistakes and inspiring me to start rowing more :) . All of my fellow graduate students and especially Courtney Kloske PhD, Holden Williams PhD, and Charles Seeks, it was so awesome having you three to battle through PGY 502/602.
My supporting family Nana, Babu, Ma Ketto, Grandpa Tree, Keeley, Sarah, Dylan and Silas (Ratboy) and of course all of your families. My love Rebecca and the two most entertaining creative, crazy, curious and kind souls ever to be put on Earth, Ellie and Calliope- I LOVE you all Finally, I wish to thank the respondents of my study (who remain anonymous for confidentiality purposes)
