Exercise-Induced Alterations in Skeletal Muscle, Heart, Liver, and Serum Metabolome Identified by Non-Targeted Metabolomics Analysis

Abstract

Background: The metabolic and physiologic responses to exercise are increasingly interesting, given that regular physical activity enhances antioxidant capacity, improves cardiac function, and protects against type 2 diabetes. The metabolic interactions between tissues and the heart illustrate a critical cross-talk we know little about. Methods: To better understand the metabolic changes induced by exercise, we investigated skeletal muscle (plantaris, soleus), liver, serum, and heart from exercise trained (or sedentary control) animals in an established rat model of exercise-induced aerobic training via non-targeted GC-MS metabolomics. Results: Exercise-induced alterations in metabolites varied across tissues, with the soleus and serum affected the least. The alterations in the plantaris muscle and liver were most alike, with two metabolites increased in each (citric acid/isocitric acid and linoleic acid). Exercise training additionally altered nine other metabolites in the plantaris (C13 hydrocarbon, inosine/adenosine, fructose-6-phosphate, glucose-6-phosphate, 2-aminoadipic acid, heptadecanoic acid, stearic acid, alpha-tocopherol, and oleic acid). In the serum, we identified significantly decreased alpha-tocopherol levels, paralleling the increases identified in plantaris muscle. Eleven unique metabolites were increased in the heart, which were not affected in the other compartments (malic acid, serine, aspartic acid, myoinositol, glutamine, gluconic acid-6-phosphate, glutamic acid, pyrophosphate, campesterol, phosphoric acid, creatinine). These findings complement prior studies using targeted metabolomics approaches to determine the metabolic changes in exercise-trained human skeletal muscle. Specifically, exercise trained vastus lateralus biopsies had significantly increased linoleic acid, oleic acid, and stearic acid compared to the inactive groups, which were significantly increased in plantaris muscle in the present study. Conclusions: While increases in alpha-tocopherol have not been identified in muscle after exercise to our knowledge, the benefits of vitamin E (alpha-tocopherol) supplementation in attenuating exercise-induced muscle damage has been studied extensively. Skeletal muscle, liver, and the heart have primarily different metabolic changes, with few similar alterations and rare complementary alterations (alpha-tocopherol), which may illustrate the complexity of understanding exercise at the organismal level.

Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation

“…Although both endurance and resistance exercise lead to fat loss (Benito et al, 2015), resistance but not endurance exercise increases muscle mass and resting metabolic rate (Poehlman et al, 1991(Poehlman et al, , 2002Dolezal & Potteiger, 1998;Hunter et al, 2000), providing better weight loss maintenance in long-term observation. There have been numerous analyses of plasma metabolites following acute endurance exercise in both clinical and animal models (Lewis et al, 2010;Huffman et al, 2014;Aguer et al, 2017;Duft et al, 2017;Starnes et al, 2017;Sato et al, 2019), which has generated a number of metabolomics "signatures" in the circulation. These plasmas metabolic profiles provide signatures of endurance exercise performance and cardiovascular disease susceptibility and also identify molecular pathways that may modulate the salutary effects on cardiovascular function.…”

Physical activity reduces anxiety and regulates brain fatty acid synthesis

“…For example, plasma indicators of the TCA cycle (succinate, malate, and fumarate), lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) were changed in exercised volunteers [45]. Selected compounds distinguished by us in the hippocampus and the FC were also changed in the skeletal (fructose-6-phosphate, 2-aminoadipic acid, heptadecanoic acid, stearic acid and oleic acid) and cardiac (malic acid, creatinine) muscles of exercised rats [46].…”

“…Among the pool of significantly changed metabolites identified herein (16 in the hippocampus and 15 in the FC), only selected compounds were previously found to be impacted by exercise in human plasma [45] and in the peripheral tissues of non-human origin [46]. For example, plasma indicators of the TCA cycle (succinate, malate, and fumarate), lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) were changed in exercised volunteers [45].…”

A mini review: Proteomics approaches to understand disused vs. exercised human skeletal muscle

“…Therefore, elucidating the mechanisms that 1) determine the molecular pathways altered by disuse, 2) determine basal muscle function and fitness (and thereby enable physical activity), and 3) mediate activityinduced skeletal muscle responses is important for finding new ways to target disuse muscle atrophy and metabolic deregulation. To understand molecular pathways regulated by disuse and exercise, multi-omics approaches have been employed in the field, such as genomics, transcriptomics, metabolomics, and proteomics (39,40,53,59,61). Given that protein expression and function are modulated by translation and posttrans-lational modifications, proteomics analysis provide a global snapshot of how the proteome is changed or altered in physiological and pathophysiological conditions.…”