Principles of Exercise Prescription, and How They Influence Exercise-Induced Changes of Transcription Factors and Other Regulators of Mitochondrial Biogenesis

Abstract

Physical inactivity represents the fourth leading risk factor for mortality, and it has been linked with a series of chronic disorders, the treatment of which absorbs ~ 85% of healthcare costs in developed countries. Conversely, physical activity promotes many health benefits; endurance exercise in particular represents a powerful stimulus to induce mitochondrial biogenesis, and it is routinely used to prevent and treat chronic metabolic disorders linked with sub-optimal mitochondrial characteristics. Given the importance of maintaining a healthy mitochondrial pool, it is vital to better characterize how manipulating the endurance exercise dose affects cellular mechanisms of exercise-induced mitochondrial biogenesis. Herein, we propose a definition of mitochondrial biogenesis and the techniques available to assess it, and we emphasize the importance of standardizing biopsy timing and the determination of relative exercise intensity when comparing different studies. We report an intensity-dependent regulation of exercise-induced increases in nuclear peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, nuclear phosphorylation of p53 (serine 15), and PGC-1α messenger RNA (mRNA), as well as training-induced increases in PGC-1α and p53 protein content. Despite evidence that PGC-1α protein content plateaus within a few exercise sessions, we demonstrate that greater training volumes induce further increases in PGC-1α (and p53) protein content, and that short-term reductions in training volume decrease the content of both proteins, suggesting training volume is still a factor affecting training-induced mitochondrial biogenesis. Finally, training-induced changes in mitochondrial transcription factor A (TFAM) protein content are regulated in a training volume-dependent manner and have been linked with training-induced changes in mitochondrial content.

Repeatability of exercise‐induced changes in mRNA expression and technical considerations for qPCR analysis in human skeletal muscle

“…Based on temporal (Egan et al., ; Perry et al., ; Serpiello et al., ; Stepto et al., ) and correlational (Bonafiglia et al., ; Raue et al., ) relationships between acute changes in mRNA expression and chronic skeletal muscle adaptation, mRNA expression is frequently used as a primary outcome measure when determining the effectiveness of an acute exercise stimulus or when comparing exercise protocols that vary in intensity, duration, and/or volume (Granata et al., ; Islam et al., ; MacInnis et al., ; Miller et al., ). Further, as awareness of training response heterogeneity and interest in personalized exercise prescription has increased, changes in mRNA expression have also been examined at the individual level (Bamman et al., ; Osler et al., ; Teran‐Garcia et al., ; Timmons et al., ,b).…”

“…For example, increases in mRNA expression following acute exercise precede chronic increases in mitochondrial protein content (Egan, O'Connor, Zierath, & O'Gorman, ; Perry et al., ; Serpiello et al., ; Stepto et al., ) and correlate with training‐induced increases in muscle size, strength (Raue et al., ) and oxidative capacity (Bonafiglia et al., ). These finding have led to the assumption that larger increases in mRNA expression following acute exercise represent a greater activation of adaptive processes underlying skeletal muscle remodelling (Granata, Jamnick, & Bishop, ; Islam, Edgett, & Gurd, ; MacInnis et al., ; Miller, Konopka, & Hamilton, ). Thus, there is interest in examining factors that may explain inter‐individual variation in mRNA expression following acute exercise (Bajpeyi et al., ) and in comparing mRNA profiles between high and low responders for training‐induced changes in cardiorespiratory fitness (Timmons et al., ,b), blood glucose regulation (Osler et al., ; Teran‐Garcia, Rankinen, Koza, Rao, & Bouchard, ), and muscle hypertrophy (Bamman, Petrella, Kim, Mayhew, & Cross, ).…”

“…Thus, there is interest in examining factors that may explain inter‐individual variation in mRNA expression following acute exercise (Bajpeyi et al., ) and in comparing mRNA profiles between high and low responders for training‐induced changes in cardiorespiratory fitness (Timmons et al., ,b), blood glucose regulation (Osler et al., ; Teran‐Garcia, Rankinen, Koza, Rao, & Bouchard, ), and muscle hypertrophy (Bamman, Petrella, Kim, Mayhew, & Cross, ). However, apart from correlational evidence (Bonafiglia et al., ; Raue et al., ), there is no direct evidence linking acute changes in mRNA expression and training‐induced adaptations (Granata et al., ; Timmons, ).…”

CrossTalk opposing view: Exercise training volume is more important than training intensity to promote increases in mitochondrial content

“…This seminal work inspired others to investigate the effects of different volumes and intensities of exercise on mitochondrial biogenesis using a range of techniques (as reviewed in Granata et al . ). The ‘gold standard’ method for assessing mitochondrial content is transmission electron microscopy (TEM), which can be used to calculate mitochondrial volume density (Mito VD ) or mitochondrial fractional area (Larsen et al .…”

Exercise twice‐a‐day potentiates markers of mitochondrial biogenesis in men

“…[1][2][3][4][5][6][7][8] While these responses are affected by the nature of the exercise (eg, the exercise intensity 2,9,10 ), there is evidence substrate availability is also a potent modulator of this response. [1][2][3][4][5][6][7][8] While these responses are affected by the nature of the exercise (eg, the exercise intensity 2,9,10 ), there is evidence substrate availability is also a potent modulator of this response.…”