OBJECTIVE: Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (n = 17) as nonresponders (n = 6) or responders (n = 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training. RESEARCH DESIGN AND METHODS: PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (31P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (Vo2peak), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs. RESULTS: By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA1c) worsened. In responders, insulin sensitivity improved. Vo2peak improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals. CONCLUSIONS: A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.
OBJECTIVE: Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (n = 17) as nonresponders (n = 6) or responders (n = 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training. RESEARCH DESIGN AND METHODS: PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (31P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (Vo2peak), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs. RESULTS: By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA1c) worsened. In responders, insulin sensitivity improved. Vo2peak improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals. CONCLUSIONS: A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.
Authors: Elvis A Carnero; Christopher P Bock; Giovanna Distefano; Karen D Corbin; Natalie A Stephens; Richard E Pratley; Steven R Smith; Bret H Goodpaster; Lauren M Sparks Journal: Diabetologia Date: 2021-08-17 Impact factor: 10.122
Authors: Melissa L Erickson; Jacob M Allen; Daniel P Beavers; Linda M Collins; Karina W Davidson; Kirk I Erickson; Karyn A Esser; Matthijs K C Hesselink; Kerrie L Moreau; Eric B Laber; Charlotte A Peterson; Courtney M Peterson; Jane E Reusch; John P Thyfault; Shawn D Youngstedt; Juleen R Zierath; Bret H Goodpaster; Nathan K LeBrasseur; Thomas W Buford; Lauren M Sparks Journal: Geroscience Date: 2022-10-15 Impact factor: 7.581
Authors: Rick B Vega; Bram Brouwers; Stephanie A Parsons; Natalie A Stephens; Maria F Pino; Andrew Hodges; Fanchao Yi; Gongxin Yu; Richard E Pratley; Steven R Smith; Lauren M Sparks Journal: Physiol Rep Date: 2020-06
Authors: Andrea M Brennan; Robert A Standley; Fanchao Yi; Elvis A Carnero; Lauren M Sparks; Bret H Goodpaster Journal: Front Endocrinol (Lausanne) Date: 2020-09-10 Impact factor: 5.555
Authors: Maria Keller; Anat Yaskolka Meir; Stephan H Bernhart; Yftach Gepner; Ilan Shelef; Dan Schwarzfuchs; Gal Tsaban; Hila Zelicha; Lydia Hopp; Luise Müller; Kerstin Rohde; Yvonne Böttcher; Peter F Stadler; Michael Stumvoll; Matthias Blüher; Peter Kovacs; Iris Shai Journal: Genome Med Date: 2020-11-16 Impact factor: 11.117