Mitochondrial adaptations to endurance training – Zac van Heerden

Mitochondria are known as the powerhouses of our cells and one goal of endurance training has always been to increase their biogenesis. To bring us up-to-date with the amazing adaptability of these special organelles, especially within a training perspective, exercise physiologist Zac van Heerden takes us on a fascinating journey of enquiry.

Mitochondria are the energy powerhouse of mammalian tissue, and the primary drivers of bioenergetic reactions that fuel various forms of physical exertion – they are essential organelles located in the intracellular space of the majority of functional cells. For the purposes of this summary, the focus will be on mitochondrial function in human skeletal muscle, and particularly on the association with exercise and metabolism. An understanding of the complex and dynamic function of the mitochondrial system in relation to exercise stress will be our starting point.

From a simplistic perspective, mitochondria are responsible for the production of simplified energy substrates (particularly ATP), derived from the metabolism of more complex molecules (carbohydrates, fats and amino acids) – they utilise oxygen to fuel this process. They differ in size, quantity and functional quality, determined by genetic factors and reactions to metabolic stress (particularly in relation to the form and duration of physical exertion) applied to an individual. They are also highly susceptible to environmental factors, ageing processes, biochemical changes and responses to various forms of stress (1,3,5).

Research into the unique and variable function of the mitochondria commenced with groundbreaking work in the late 1960s. Over the past half-decade, with the advent of improved technology and methodology to evaluate and measure intracellular function, new concepts have broken the longstanding view that all mitochondria were ‘created equal’ and that the extend of individual modification was limited (1,3,5).

There is compelling evidence that bouts of acute exercise result in significant metabolic changes to mitochondrial processes, and impact directly on the phenotypic expression at the sub-cellular level, particularly in relation to mitochondrial RNA (mtRNA) transcription of protein-based complexes within the mitochondrial networks (1,3,5).

Recent research into mitochondrial function and adaptation has focused on elements such as the effect of contractile activity on mitochondrial biogenesis, as well as biochemical changes and adjustments to transcription and regulatory factors, with a particular focus on the roles of mitochondrial DNA and RNA (mtDNA/mtRNA). The following biochemical and genetic factors deserve mention as key contributors to the adaptive processes, and although outside the ambit of a succinct discussion, a deeper understanding of their functional roles is recommended (1,3,5):

 

• • Nuclear genome sequences (mtDNA)

• • Specific mitochondrial genetic sequences (mtRNA)

• • Mitochondrial transcription factor A (TFAM)

• • Peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a)

• • AMP-activated protein kinase (AMPK)

• • Nuclear respiratory factor-1 (NRF-1)

Location and function of the mitochondria

In skeletal muscle, there are two forms: mitochondria form a network of interconnected mitochondria underneath the sarcoplasm (subsarcolemmal mitochondria) and groups interspersed within the space between myofibrils (intermyofibrillar mitochondria) (1,3,5).

The traditional theoretical model of cell biology presents the mitochondria as separate and independent organelles within a cell structure – it is more accurate to view this as a networked and interdependent system – the muscular mitochondrial reticulum – that extends into and around active regions of the skeletal muscle architecture (1,3,5).

The subsarcolemmal subpopulation are closer to the site of oxygen transfer during internal respiration at the blood-tissue boundary, and are therefore logically more likely suited to the production of energy involving aerobic processes – whereas the intermyofibrillar group are exposed to a greater degree of anaerobic processes and exposure to acidic effects close to the contractile site. There is a distinct possibility that this differentiation of functional roles may have a significant impact on expression and alteration of enzyme structures produced by the mtRNA processes (1,3,5).

Energetic adaptations to exercise

An important concept to grasp is the functional difference between mitochondrial volume and density (quantity) and that of functional quality – specific training will result in increases in volume, but of greater impact are functional alterations. These changes involve increases in biochemical factors, changes to regulatory aspects (expression of mtRNA processes and transcription to protein-based structures), developmentof interconnected networks to share and distribute precursors and products, and the programmed destruction and recycling of damaged or dysfunctional components (1,3,5).

Mitochondrial biogenesis (mitogenesis) is defined as the ‘life cycle’ of the mitochondria, involving the cellular processes active during the structural formation, through to the eventual degradation and its removal. During its active functional phases, the structure can undergo fusion (linkage with other mitochondria), fission (splitting), and a complex process of reticulation (networking). Once function declines, the process of mitophagy (destruction and recycling) is initiated, primarily under the influence of intracellular nuclear processes (1,3,5).

Increased ATP turnover and ‘leakage’ of ionic calcium (Ca⁺⁺) are both established events during sustained contractile activity – this stimulates the chain of events that lead to mitogenesis. This process involves mechanical and biochemical processes, including enzyme activation, tissue modification factors, genetic transcription, and ultimately physical/structural changes to the mitochondrial networks. For the purposes of brevity we will not go into additional detail on these processes, but additional reading may be valuable to fully grasp the capacity and time-course of adaptive responses and processes (1,3,5).

Endurance training logically results in increased activity and metabolic function, affecting mitochondrial processes. This increases the rate of mitochondrial turnover (development and destruction) – increases in all elements of mitochondrial biogenesis (fusion, fission, reticulation and mitophagy) will result (1,3,5).

With endurance training, mitochondrial volume and density can increase by up to 40 per cent and is primarily related to an increase in the intermyofibrillar group. Adaptations to functional capacity appear to depend on the intensity of training and can generally 
be explained by an increased expression of mitochondrial enzymes that facilitate aerobic metabolism. Although mitochondrial volume increases with training, the improvement in reticulation and chemical transfer within the mitochondrial network is a more significant adaptation – this is explained by the limited impact of increased mitochondrial volume
 on maximal oxygen uptake, whereas there are potentially massive changes to exercise efficiency and utilisation of oxygen and energy at submaximal levels as a consequence of specific training (1,3,5).

The time course of mitochondrial development is fairly rapid: mitochondrial protein half-life is in the region of seven to ten days and structural phospholipid components (external and internal membrane structure) have a half-life of four days. Construction and regeneration of mitochondrial architecture and biochemistry is a quick process and improvements in functional capacity can be realised in a short time span. Chemical and structural stability is generally reached in approximately six to eight weeks – this has important implications for exercise prescription and nutritional considerations (1,3,5).

Other aspects of exercise-mediated changes involve a range of genetic processes, with most recent literature investigating the role of mtRNA transcription and potential short-term mutation. It appears that an individual may experience functional changes to the way in which intracellular protein metabolism takes place – this may explain many of the differences between aerobic and non-aerobic adaptations to different forms of training and the relative ‘permanence’ of physiological capacities built up through regular training (1,3,5).

Mitochondrial stabilisation is a key part of this process – a shift in the regulation of enzymes and protein coding processes, under the duress of exercise stress, is required 
to maintain differences to function over a significant time period. A four to eight week exposure is likely to be necessary to result in more permanent adaptation, and genetics is likely to play a role on the speed and degree of response (1,3,5).

Interestingly, low-load resistance exercise has also been shown to stimulate mitochondrial changes, more so than what would have been expected from the relative contribution to energy metabolism from anaerobic processes. Changes to mitochondrial volume and reticulation are significantly similar to aerobic stimuli, although it is likely that the biochemical changes are more geared towards anaerobic function (2).

Genetic predisposition to mitochondrial adjustment

The nuclear genome encodes most of the genes for mitochondrial architecture and biochemistry, whereas the mitochondria possess an independent genome (with direct maternal heritability), consisting of 37 specific genes. 13 of these genes encode essential proteins to the respiratory processes required for energy metabolism. Certain individuals are thus likely to have a higher genetic capacity for mitochondrial adjustment, and a predisposition to changes geared towards particular forms of training – a direction for additional research in this area (1,3).

Peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a) and mitochondrial transcription factor A (TFAM) are not the only genetic components involved in this process, but are potentially key factors to understanding the regulation and coordination of the genetic response to exercise stresses (1,3,5).

PGC-1a is a key regulator of the transcription of mitochondrial genes, and has been implicated in the changes to mitochondrial biogenesis – along with TFAM, it has become a commonly used marker of skeletal muscle adaptation to exercise training (1,3,5).

TFAM is an essential modulator of mitochondrial adaptation, and is transported into the mitochondrial network as part of the micro-adaptive exercise effect, where it controls the expression of mtDNA. Contractile activity increases TFAM expression and accelerates its import into mitochondria, resulting in increased mtDNA transcription and replication (1,3,5).

Impact of environmental factors and the ageing process

Mitochondrial systems are sensitive to a range of other biochemical conditions, including (1,3,7,8):

 

• • The effect of altitude (hypoxia/hyperoxia and barometric pressure changes)

• • Temperature-related stresses (especially due to enzyme volatility)

• • The influence of chemical products (not only pH, but also concentrations of the products of oxidation and other molecules that may accelerate or inhibit complex chemical processes).

It is possible that the concomitant application of these type of stresses (one or more) with physical exertion will modify the adaptive effects discussed up to this point. Whether these combinations enhance or reduce adaptation is unclear, and is a route for further investigation.

The mitochondria have been shown to suffer a similar fate to other cellular components with regard to the effects of the ageing process. Increased systemic inflammation (and the chemical interference thereof), along with reductions in growth factors (such as human growth hormone and insulin-like growth factor 1) and specific components of the endocrine system result in decreased biogenesis, increased mitophagy and dysfunctional components (7,8).

Despite the short-term improvements that have been noted, does exercise adaptation accelerate or delay the impact of long-term ageing-related mitochondrial dysfunction? Investigations done on healthy older subjects suggest that decreases in gene expression
 and the role of PGC-1a is associated with mitochondrial dysfunction in the skeletal muscle. This decline can be attributed to age-related disruption in the regulatory pathways of enzyme actions, such as AMP-activated protein kinase (AMPK). Nutritional and pharmaceutical interventions can therefore play a significant role in enhancing the effects of physical activity, despite the impact of ageing processes (7,8).

How training and nutrition impacts our mitochondria 

Intramuscular fat is found in the form of lipid droplets of triacylglycerol, stored in the intermyofibrillar space, in close proximity to the mitochondria, which are able to metabolise energy from this readily available source. Intramuscular triacylglycerolysis (IMTG) is a process that stimulates metabolism and energy production from lipid substrates within skeletal muscle. During exercise, sufficient oxygen supply is required to fuel this process – lower intensity work at a consistent rate will provide the best conditions for the utilisation of intramuscular triacylglycerol, which may contribute up to 20 per cent of total energy turnover (depending on diet, gender, and the type of exercise involved) (4,6).

Research has revealed that lower-calorie dietary intake and the role of exercise-induced (sterol regulatory element-binding) proteins are involved in the elevated levels of IMTG in athletes. In contrast, higher-weight individuals display a build-up of IMTG in different regions of the muscle, and this correlates to high levels of general adipose tissue – sedentary subjects lack the refined and improved mitochondrial processes required to metabolise these fats, which can result in this accumulation. Correct training (low-intensity, with a duration that doesn’t induce significant fatigue stress) will assist in improving this. Further studies have shown that women have a higher IMTG content and have revealed that they may use more fat-based metabolism during exercise (4,6).

As mentioned previously, a six week adjustment and stabilisation period is increasingly being seen as key in improving and adjusting metabolic function. Consistent and regular training at appropriate prescriptive levels (utilising heart rate monitoring or similar methodologies to control intensity and duration) are recommended to maximise the effects. The use of genetic testing to establish individual capacity for mitochondrial adjustment may also be of value in the design and prescription of tailored training plans (1,4,6).

In conclusion, mitochondria are essential and dynamic components of a healthy metabolic system. To maximise physical performance and overall health across the lifespan, there is a requirement for integrated methodologies that incorporate appropriate training, nutrition, rest and recovery. Future research and investigation will aid in identifying and streamlining these relationships to maximum effect.