Regulation of Proteins in Human Skeletal Muscle: The Role of Transcription

Abstract

Regular low intensity aerobic exercise (aerobic training) provides effective protection against various metabolic disorders. Here, the roles played by transient transcriptome responses to acute exercise and by changes in baseline gene expression during up-regulation of protein content in human skeletalmuscle were investigated after 2 months of aerobic training. Seven untrained males were involved in a 2 month aerobic cycling training program. Mass-spectrometry and RNA sequencing were used to evaluate proteome and transcriptome responses to training and acute exercise. We found that proteins with different functions are regulated differently at the transcriptional level; for example, a training-induced increase in the content of extracellular matrix-related proteins is regulated at the transcriptional level, while an increase in the content of mitochondrial proteins is not. An increase in the skeletal muscle content of several proteins (including mitochondrial proteins) was associated with increased protein stability, which is related to a chaperone-dependent mechanism and/or reduced regulation by proteolysis. These findings increase our understanding of the molecular mechanisms underlying regulation of protein expression in human skeletal muscle subjected to repeated stress (long term aerobic training) and may provide an opportunity to control the expression of specific proteins (e.g., extracellular matrix-related proteins, mitochondrial proteins) through physiological and/or pharmacological approaches.Metabolic syndrome and type 2 diabetes mellitus are among the most widespread diseases in Western countries. Regular low intensity aerobic exercise (aerobic training) improves insulin sensitivity, fat metabolism, and endurance. This effect is associated mainly with a marked increase in skeletal muscle mitochondrial volume/density, increased amounts and activity of mitochondrial enzymes, and increased fat oxidation in muscle both at rest and during low intensity exercise 1-4 . Therefore, investigation of the molecular mechanisms underlying skeletal muscle adaptation to regular aerobic exercise (aerobic training) is of fundamental importance.Acute stress (e.g., each individual exercise session) is associated with transient (over several hours) changes in gene expression in cells; hence, repeated exposure to stress leads to an increase in expression of specific proteins and cellular functions 5,6 . However, regular aerobic exercise is associated not only with a transient transcriptome response after each exercise session, but also with a pronounced change in expression of a large number of genes under baseline conditions 7-9 . Therefore, both repeated responses to acute exercise and changes in baseline gene expression might regulate the tissue content of different proteins. Recent studies examined the role of baseline mRNA levels in regulating proteins in cells [see the review 6 ] and, to a lesser extent, in various human tissues 10-12 . However, to the best of our knowledge, only one study has examined the role of mR...

Transcriptomic Signatures and Upstream Regulation in Human Skeletal Muscle Adapted to Disuse and Aerobic Exercise

“…Notably, a previous study found that the same number of genes encoding mitochondrial proteins were expressed at lower levels in sarcopenic human VL muscle showing low mitochondrial density than in age-matched controls [ 70 ]. In agreement with our previous findings [ 20 , 35 ], our current analysis revealed that acute and regular exercise induced the expression of only a few genes (2% and 3%) encoding mitochondrial proteins ( Figure 3 a, Table 2 and Table S4 ). It is possible that acute exercise-induced up-regulation of these genes may occur in the latter stages of recovery.…”

“…Here, we found that regular aerobic exercise substantially up-regulated more than a half of genes encoding muscle collagens, as well as a number of ECM glycoproteins and proteoglycans (47 genes in total: 56%, 25% and 32% of the corresponding genes, respectively), including the two most abundant muscle ECM proteins: collagen alpha-1 (I and III) accounting for more than half of the ECM proteins in skeletal muscle [ 60 ] ( Figure 3 b, Table 2 and Table S4 ). These responses were predominantly related to changes in the baseline gene expression induced by long-term training and support the notion that ECM proteins are closely regulated at a transcriptional level [ 35 ]. Only a few enzymatic ECM regulators are known to be involved in disuse- and training-induced ECM remodeling in skeletal muscle (reviewed in [ 46 , 47 ]).…”

“…In the human VL muscle, acute and regular aerobic exercise increases the collagen synthesis rate [ 56 ] and concentrations of collagens (reviewed in [ 46 ]) and other ECM proteins [ 35 ]. Regular aerobic exercise probably has a weak effect on the viscoelastic properties of the muscle–tendon unit [ 57 , 58 ], but substantially reduces exercise-induced muscle damage and soreness (reviewed in [ 59 ]) associated with changes in the ECM and endomysium.…”

“…Disuse negatively regulates the ability of muscle to oxidize fat and carbohydrate, as well as mitochondrial density and function, and thereby decreases aerobic performance (reviewed in [ 41 , 49 ]). By contrast, regular aerobic exercise markedly increases these parameters [ 42 ], as well as the concentrations of numerous enzymes related to lipid transport and beta oxidation, the citrate cycle and oxidative phosphorylation, but has no marked effect on the levels of glycolytic enzymes [ 35 , 36 , 50 ]. Here, we found that disuse and exercise weakly affected glycolysis at the transcriptional level in a multidirectional manner by regulating a gene called LDHB .…”

Skeletal Muscle Extracellular Matrix – What Do We Know About Its Composition, Regulation, and Physiological Roles? A Narrative Review

“…In this respect, it has been shown that protein expression in skeletal muscle is weakly regulated at the mRNA level leading to big differences in mRNA and protein abundance in various tissues (Wang et al, 2019). Interestingly, the pattern of protein regulation depends on protein function, whereby the association between mRNA and protein is higher for ECM and collagen fibril organization (Makhnovskii et al, 2020). Another interesting aspect in the regulation of the amount of ECM proteins is the fact that induction of transcription seems to be rather slow for collagen as it takes almost 3 days to fully induce transcription.…”