Mitochondrial adaptations to exercise in human skeletal muscle: a possible role for cristae density as a determinant of muscle fitness

Skeletal muscle possesses a remarkable plasticity in response to repeated exercise challenges (i.e. exercise ‘training’). A hallmark phenotypic change is an increase in the ability to sustain contraction and resist fatigue. Such increased muscle endurance is linked, in part, to an improved ability to sustain ATP synthesis aerobically through coordinated enhancements in the delivery of oxygen (e.g. cardiorespiratory, vascular adaptations) and its utilization within skeletal muscle mitochondria for the oxidation of fat and carbohydrates. With respect to the latter, a prevailing model developed by John Holloszy nearly 50 years ago (Holloszy, 1967) proposes that an increased mitochondrial content within muscle itself improves the degree to which a rise in ADP during contraction will stimulate its oxidative phosphorylation to ATP. The result is a metabolic shift in skeletal muscle whereby more sustainable aerobic oxidation of fats and carbohydrates occurs in lieu of less sustainable substrate phosphorylation. Thus, the model suggests that exercise training increases muscle endurance because a greater mitochondrial content improves oxidative ATP supply to energy‐dependent processes during contraction.

Distinct from the concept that mitochondrial content influences muscle endurance was the emerging observation that exercise training also lengthens the mitochondrial reticulum in rodent muscle (Kirkwood et al. 1987) possibly through increased expression of proteins regulating mitochondrial morphology as observed in human skeletal muscle during training (Cartoni et al. 2005; Perry et al. 2010). Indeed, human skeletal muscle mitochondria are known to exist in an elongated reticulum, as was shown by striking three‐dimensional electron microscopy nearly 20 years ago (Ogata & Yamasaki, 1997), suggesting mitochondrial structure and function may be inter‐related. Extensive research thereafter has shown that fused and elongated mitochondria are associated with greater capacities for oxidative phosphorylation, rather than fragmented mitochondria (Bach et al. 2003; Pernas & Scorrano, 2016).

In this issue of The Journal of Physiology, a paper by Nielsen et al. (2017) extends these questions regarding the distinct role of mitochondrial morphology vs. content as mediators of the improved endurance that follows exercise training. This paper addresses our lack of understanding regarding morphological changes within mitochondria themselves, which seems to be traced back to classic assumptions that cristae density is a fixed constant (see discussion by Nielsen et al.). As such, the degree to which mitochondrial cristae structure adapts to exercise has been surprisingly underexplored in human skeletal muscle. As the authors note, the pioneering electron microscopy work by several groups over the last 40 years has quantified and described the precise degree to which mitochondrial content increases in human skeletal muscle following different combinations of exercise training. However, mapping cristae dynamics in particular may be critical for understanding the manner by which oxidative phosphorylation is enhanced given these membranous structures are the precise location of the electron transport system amongst other critical regulators of metabolism.

It is within this context that the recent work by Nielsen et al. (2017), from Ortenblad's group, carries significant impact. Using human skeletal muscle, these researchers demonstrate that mitochondrial cristae become denser following long‐term exercise training. Moreover, they show that mitochondrial cristae density is a stronger predictor of maximal oxygen consumption (i.e. ${\dot{V}}_{{\mathrm{O}}_2\max }$) than the classic predictor of mitochondrial volume or content. The authors present an intriguing proposal that increased mitochondrial density may be an efficient mechanism of increasing the capacity for oxidative phosphorylation in light of the limited subcellular space that is largely dominated by myofibrillar structures. In other words, increasing cristae density may be a more efficient use of space than increasing mitochondrial content, and might prevent reductions in force per unit area that would otherwise happen if even greater increases in mitochondrial volumes occurred.

These proposals are compelling and demonstrate how the work by Nielsen and co‐authors identified an important missing link in our understanding of mitochondrial adaptations to exercise training. The observations were reported in human skeletal muscle, which provides direct translational relevance to understanding how exercise training increases human muscular endurance. By providing a detailed reference of basic cristae modifications during exercise in humans, the investigation may serve as a foundation to compare cristae adaptability in future studies. For example, intriguing questions arise regarding the adaptability of cristae density in various diseases following exercise interventions (explored to some extent in obese and diabetic populations in their investigation), or the temporal kinetics that regulate cristae dynamics. Moreover, the precise regulatory mechanisms of cristae remodelling remain to be explored, but may be linked to the known governance by mitochondrial fusion and fission proteins (Pernas & Scorrano, 2016).

For the present time, this investigation adds an important contribution to the last ∼50 years of research that positions mitochondrial plasticity as a critical process that improves muscle endurance following exercise training in humans.

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Competing interests

None declared.