The ability of aerobic exercise training to promote mitochondrial biogenesis – “the making of new components of the mitochondrial reticulum” [1] – and improve mitochondrial respiratory function – “qualitative changes in organelle function” [2] – is well characterized. Mitochondrial biogenesis is triggered by acute (i.e. response following a single exercise bout) activation of the mitochondrial protein synthetic pathway: (1) altered primary messengers that reflect transient changes in muscle homeostasis, (2) intramuscular signalling cascades that activate transcriptional proteins controlling mitochondrial gene expression, (3) transcriptional regulation (↑ mRNA expression of genes encoding mitochondrial proteins), (4) synthesis of new mitochondrial protein, and (5) post-translational processing and integration of new mitochondrial protein into the mitochondrial reticulum [2], [3], [4]. When acute bouts of exercise are undertaken successively in close proximity (i.e. exercise training) mitochondrial content and function are increased and skeletal muscle performance and health are improved [5]. Although the ability of exercise to induce mitochondrial biogenesis is accepted, the optimal exercise prescription (volume, intensity, duration, and frequency of training) and the molecular pathways underlying the optimal response remain topics of great discussion [6], [7], [8].

Both training Intensity [9] (the amount of work performed per unit of time) and training Volume [7] (the product of exercise intensity, exercise duration [time per session]) have been postulated to be the most important determinant of mitochondrial biogenesis. Isolating the effect of exercise intensity is complicated by the fact that exercise at elevated exercise intensities is accompanied by elevated exercise volume unless exercise duration is reduced. Thus, although the primary means of experimentally augmenting training volume is to increase exercise duration, increases in intensity may also need to be interpreted within the context of increased exercise volume. Although it appears that both intensity and volume are important for chronic increases in mitochondrial content/function [5], and that intensity may contribute more than volume to the acute activation of mitochondrial biogenesis [6], the relative impacts of altered volume, intensity and duration on primary messengers, intramuscular signaling, and transcriptional regulation have not been comprehensively explored.

The initiation of mitochondrial biogenesis occurs in response to contraction induced disruption of muscular homeostasis. As described above, mitochondrial biogenesis is initiated by alterations in primary messengers and a complex network of intramuscular signaling cascades (reviewed in [2], [10]). The cellular energy sensor AMP-activated protein kinase (AMPK) is activated by changes in the intramuscular phosphorylation potential ([ADP][AMP]:[ATP] ratio) and contributes to the activation of downstream protein involved in the transcriptional control of mitochondrial biogenesis [11], [12], [13]. Similarly, the Calcium/calmodulin serine/threonine kinase (CaMK) signaling pathway interacts with downstream regulators of transcription following increases in intramuscular calcium associated with muscle contraction [13], [14], [15]. Specifically, CaMK responds to increases in cytosolic Ca2+ by activating mitochondrial protein synthesis via a pathway that includes p38 MAPK [16], [17]. AMPK and CaMK signaling converge on the transcription factor co-activator peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) – the purported master regulator of mitochondrial biogenesis [13], [18], [19], [20]. When active, PGC-1α coordinates the upregulation of nuclear and mitochondrial encoded genes [21] thus contributing to the induction of mitochondrial biogenesis. Importantly, PGC-1α autoregulates it’s own gene expression allowing changes in PGC-1α mRNA to be used as a proxy for PGC-1α transcriptional activity [18].

The purpose of this review is to present and discuss the impacts of augmented training volume, intensity, and duration on the phosphorylation/activation of key signaling protein – AMPK, CaMKII – and on post exercise increases in PGC-1α mRNA expression. We will attempt to answer the question: “when augmenting training volume, does increased intensity or increased duration elicit greater activation of factors involved in the initiation of mitochondrial biogenesis?”. We will examine changes in the intramuscular primary messengers ADP and AMP and calcium (Ca2+) (Section 3) and AMPK/CaMK signaling (Section 4) associated with the activation of PGC-1α and post-exercise changes in PGC-1α mRNA expression (Section 5). We will attempt to highlight studies that have isolated the effect of exercise intensity by matching total training volume and will discuss the complications of interpreting studies where both intensity and volume are augmented as evidence supporting the superiority of intensity for activating mitochondrial biogenesis. Although we will utilize evidence from animal and cellular models where required, our focus throughout this review will be on evidence gleaned from human studies.