Fig. 3 |. Molecular responses to acute exercise and exercise training.

Exercise-induced alterations in circulating molecules^19,124 and the intramuscular milieu^55,101, together with mechanical tension¹⁷⁸, initiates a temporal series of biochemical and molecular events that lead to muscle adaptation. Activation of signalling cascades promote substantial posttranslational modification of the muscle proteome^90,170 and DNA accessibility^198,199,230. Collectively, this drives transcription factor-dependent¹⁶⁹ changes in gene expression^167,183, alongside microRNAs²⁰⁴ and long-non-coding RNAs²⁰⁵ that are thought to ‘fine-tune’ the molecular responses to exercise. Endurance exercise (EE) and resistance exercise (RE) are often considered divergent stimuli, primarily driving oxidative versus hypertrophic muscle adaptations, respectively. However, common processes among exercise modalities can result in shared enrichment of signalling cascades⁹⁰ and transcriptional networks¹⁸³ in the post-exercise period. For example, coordinated proteolysis is detected following acute exercise, irrespective of exercise type⁹⁰. This may require cAMP–protein kinase A (PKA)^190,191 and ensures protein quality control and physiological muscle remodelling. 5′-AMP-activated protein kinase (AMPK) activity⁹⁰ and the expression of total PGC1A mRNA¹⁸³ are also increased after a single bout of either endurance or resistance exercise. AMPK phosphorylation activates peroxisome proliferator-activated receptor-$\text{γ}$ coactivator $1\text{α}$ isoform 1 ($\text{PGC}1{\text{α}}_1$)²⁷⁹, and both AMPK and $\text{PGC}1{\text{α}}_1$ potentiate angiogenic factors^260,280 and mitochondrial bioenergetics^{48,235,260,279} in muscle. After endurance exercise, a distinct pool of mitochondrial AMPK (composed of ${\text{α}}_1$, ${\text{α}}_2$, ${\text{β}}_2$ and ${\text{γ}}_1$ isoforms) regulates mitophagy^187–189 and promoter hypomethylation facilitates the transcription of peroxisome proliferator-activated receptor-$\text{δ}$ ($\text{PPARδ}$) and mitochondrial transcription factor A (TFAM)²³⁰. Whether resistance exercise elicits these same effects is unclear. Despite similarities, there are more distinct than overlapping post-exercise responses between modalities^90,183. Rapamycin-sensitive substrates of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) are phosphorylated to a greater extent after resistance exercise⁹⁰. Mechanical overload initiates translocation of the mTOR–lysosomal complex¹⁷⁴ and diacylglycerol (DAG) kinase-$\text{ζ}$ ($\text{DGKζ}$)¹⁷³ to the sarcolemma. Here, mTOR colocalization with RAS homologue enriched in brain (RHEB) and eukaryotic initiation factor 3 (EIF3)¹⁷⁴ and phosphatidic acid (PA) produced by $\text{DGKζ}$¹⁷³ might coalesce to fully stimulate mTORC1 (ref. 175) and the translation of contraction-associated mRNAs. Acute attenuation of UNC-51-like autophagy activating kinase 1 (ULK1) autophagic signalling after resistance exercise⁶⁵ and nuclear $\text{DGKζ}$-mediated suppression of forkhead box protein O (FOXO)-dependent proteasomal degradation could also support muscle mass by moderating the breakdown of myofibrillar proteins¹⁷³. At the sarcomere, contraction recruits $\text{ZAKβ}$ to the Z-disc¹⁷⁹ where it acts through JUN N-terminal kinase 1 (JNK1) and JNK2 (refs. 179,181), potentially alongside Notch¹⁸², to inhibit myostatin (MSTN)/transforming growth factor-$\text{β}$ ($\text{TGFβ}$) signalling. This represents one of many intracellular changes permitting resistance training-induced hypertrophy over endurance-like adaptations¹⁸¹. The upregulation of MYC with resistance exercise stimulates ribosomal biogenesis^180,198, and the formation of a specialized pool of ribosomes with a high ratio of ribosomal protein large 3 (RPL3) to RPL3-like (RPL3L)²³⁸ may favour protein synthesis over translational fidelity. MYC expression is mTOR-independent but MYC cooperation with mTOR is necessary to successfully increase ribosomal content¹⁸⁰, possibly requiring an mTOR-driven reorganization of nucleoli to aid rRNA transcription²⁸¹. Divergence between endurance and resistance exercise at the transcriptomic level is magnified after a period of training¹⁸³. Endurance training increases electron transport chain complex expression¹⁸³, mitochondrial content and muscle oxidative capacity¹². Conversely, growth-related pathways¹⁸³, ribosomal abundance¹⁹⁸ and muscle mass¹² are augmented more by resistance training. This could be mediated in part by $\text{PGC}1\text{α}$ isoforms. Nuclear localization of $\text{PGC}1{\text{α}}_1$ and Ser15 phosphorylation of p53 are greater in resting muscle after high-intensity interval training²³⁹, which might help to preserve mitochondrial content and function²⁵⁷. By contrast, $\text{PGC}1{\text{α}}_1$ protein is unchanged after resistance training, whereas the $\text{PGC}1\text{α}$ isoform 4 ($\text{PGC}1{\text{α}}_4$) protein is preferentially enriched²³⁵. $\text{PGC}1{\text{α}}_4$ stimulates muscle hypertrophy and is associated with enhanced Igf1 expression²²⁹, insulin-like growth factor 1 (IGF1)–serine/threonine protein kinase (AKT) and mTORC1 signalling²³⁴ and downregulation of Mstn mRNA in mouse muscle²²⁹. However, unlike $\text{PGC}1{\text{α}}_1$ (ref. 280), $\text{PGC}1{\text{α}}_4$ does not coactivate oestrogen-related receptor-$\text{α}$ ($\text{ERRα}$)²²⁹ and has no effect on oxidative phosphorylation enzymes^229,235. Appreciable overlap in the initial stages of exercise training probably underlies the degree of shared adaptation between endurance and resistance exercise (see the sections ‘Skeletal muscle responses to acute exercise’ and ‘Skeletal muscle adaptations to long-term exercise’). Depending on individual predisposition (Box 1), dedicated training of a certain exercise modality could amplify discrete differences in the adaptive response, resulting in distinct muscle adaptations and the development of specific phenotypes over time¹³. Evidence showing that combined endurance and resistance training can blunt muscle hypertrophy in humans is scarce^184,185 but concurrent training could impede gains in explosive strength¹⁸⁴. Still, a combined exercise regime may offer dual benefits for most individuals¹². ACTRIIB, activin receptor type 2B; ECM, extracellular matrix; MFF, mitochondrial fission factor; MCU, mitochondrial calcium uniporter; NFATc1, nuclear factor of activated T cells, cytoplasmic 1; NICD, Notch intracellular domain; NRF2, nuclear factor erythroid 2-related factor 2; p38, p38 mitogen-activated protein kinase; RPS6, ribosomal protein S6; SMAD, mothers against decapentaplegic homologue; Ub, ubiquitin; $\text{ZAKβ}$, MAP3K20 isoform-$\text{β}$.