Cardio
Narrative Review
2018
Exercise and the Regulation of Mitochondrial Turnover
By Inigo San-Millan and George A. Brooks
Progress in Molecular Biology and Translational Science, 155, pp. 25-71
<h2>Abstract</h2>
<p><a href="/terms/zone-2-training/" class="term-link" data-slug="zone-2-training" title="Zone 2 training">Zone 2 training</a>—sustained aerobic exercise performed at an intensity below the first lactate threshold (LT1), corresponding to approximately 60–70% of maximal heart rate—has emerged as a cornerstone of endurance training methodology and is increasingly recognized for its metabolic health benefits beyond athletic performance. This review examines the cellular and systemic adaptations to Zone 2 training, with particular emphasis on mitochondrial biogenesis, fat oxidation capacity, insulin sensitivity, and cardiovascular health.</p>
<p>Zone 2 training selectively recruits Type I (slow-twitch) muscle fibers, which are characterized by high mitochondrial density and oxidative capacity. Sustained training at this intensity drives mitochondrial biogenesis through activation of PGC-1α and related transcription factors, improving both mitochondrial density and function. These adaptations translate to enhanced fat oxidation capacity, reduced reliance on carbohydrate oxidation at submaximal intensities, and improved metabolic flexibility.</p>
<p>At the systemic level, Zone 2 training improves insulin sensitivity, reduces triglycerides, lowers resting heart rate, and attenuates cardiovascular risk factors. Emerging evidence suggests that mitochondrial dysfunction is a common upstream driver of metabolic disease, and that Zone 2 training's mitochondrial adaptations may confer therapeutic benefits in insulin resistance, type 2 diabetes, and metabolic syndrome. Practical programming recommendations for integrating Zone 2 training with resistance training are provided.</p>
<h2>Introduction</h2>
<p>The concept of exercise intensity zones has been a foundational element of endurance sport training methodology for decades. Among these zones, Zone 2—defined as sustained aerobic exercise below the first lactate threshold (LT1) or the ventilatory threshold (VT1)—has historically been associated with the high-volume, low-intensity base training that endurance athletes perform to build aerobic foundation. In recent years, <a href="/terms/zone-2-training/" class="term-link" data-slug="zone-2-training" title="Zone 2 training">Zone 2 training</a> has attracted broader interest as a therapeutic and health optimization modality, driven in part by growing understanding of mitochondrial biology and metabolic disease pathophysiology [1].</p>
<p>The lactate threshold represents a critical metabolic boundary. Below LT1 (Zone 2), the body primarily oxidizes fat as fuel, lactate production is balanced by clearance, and exercise can be sustained for extended durations. Above LT1, carbohydrate oxidation increasingly dominates, lactate begins to accumulate, and the duration of sustainable effort is progressively limited [2]. Zone 2 training therefore specifically challenges the oxidative machinery of Type I muscle fibers and the mitochondrial network within them, driving adaptations that are qualitatively distinct from those produced by high-intensity training.</p>
<p>Mitochondrial dysfunction has been identified as a central feature of insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease [3]. Reduced mitochondrial oxidative phosphorylation capacity, decreased fat oxidation rates, and impaired mitochondrial quality control (autophagy and biogenesis) characterize the metabolic tissue of individuals with these conditions. The premise that Zone 2 training directly targets and reverses these mitochondrial deficits positions it as a uniquely powerful preventive and therapeutic exercise modality.</p>
<p>This review examines the molecular, cellular, and systemic evidence for Zone 2 training's effects on mitochondrial function and metabolic health, with particular attention to mechanistic pathways and practical implementation strategies.</p>
<h3>References</h3>
<p>[1] San-Millan I, Brooks GA. Assessment of metabolic flexibility by means of measuring blood lactate. <em>J Appl Physiol</em>. 2018;124:1548–1560.
[2] Wasserman K, et al. Anaerobic threshold and respiratory gas exchange during exercise. <em>J Appl Physiol</em>. 1973;35:236–243.
[3] Petersen KF, et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. <em>N Engl J Med</em>. 2004;350:664–671.</p>
<h2>Mitochondrial Function and <a href="/terms/zone-2-training/" class="term-link" data-slug="zone-2-training" title="Zone 2 Training">Zone 2 Training</a></h2>
<h3>Mitochondrial Biogenesis</h3>
<p>Zone 2 training is one of the most potent stimuli for mitochondrial biogenesis in skeletal muscle. The primary molecular mediator is peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), which is activated in response to Zone 2-intensity exercise through multiple upstream signals including AMPK and calcium/calmodulin-dependent protein kinase (CaMKII) [1]. PGC-1α activates nuclear respiratory factors (NRF-1, NRF-2) and mitochondrial transcription factor A (TFAM), driving coordinated expression of both nuclear-encoded and mitochondrial-encoded components of the oxidative phosphorylation machinery.</p>
<p>Chronic Zone 2 training increases both mitochondrial density (number of mitochondria per unit muscle volume) and the functional capacity of existing mitochondria. Trained endurance athletes can have up to 2–3 times higher mitochondrial density in slow-twitch muscle fibers compared with sedentary individuals [2]. This expanded mitochondrial mass fundamentally increases the cell's capacity for oxidative phosphorylation and fat oxidation.</p>
<h3>Fat Oxidation Capacity</h3>
<p>A hallmark adaptation to Zone 2 training is enhanced fat oxidation capacity. This improvement reflects multiple integrated adaptations: increased mitochondrial density, upregulation of enzymes in the beta-oxidation pathway (including carnitine palmitoyltransferase I, which controls fatty acid entry into mitochondria), increased intramuscular triglyceride content as an immediately accessible local fat depot, and improved capacity to oxidize free fatty acids delivered from systemic circulation [3].</p>
<p>In practical terms, these adaptations allow trained individuals to oxidize fat at higher absolute exercise intensities, thereby "sparing" carbohydrate stores for the higher-intensity efforts that require them. Elite endurance athletes may maintain high rates of fat oxidation at power outputs that would saturate glycolytic pathways in untrained individuals—a critical performance advantage for prolonged exercise.</p>
<h3>Mitochondrial Quality Control</h3>
<p>Beyond biogenesis, Zone 2 training enhances mitochondrial quality control through upregulation of mitophagy (selective autophagy of damaged mitochondria) and fusion/fission dynamics [4]. Healthy mitochondrial quality control prevents accumulation of dysfunctional mitochondria that generate excess reactive oxygen species (ROS) and contribute to cellular oxidative stress. This mitochondrial quality maintenance effect may be particularly relevant to metabolic disease prevention, as dysfunctional mitochondria are increasingly implicated in the pathogenesis of insulin resistance.</p>
<h3>Lactate Dynamics</h3>
<p>An important and often overlooked aspect of Zone 2 training is its effect on lactate clearance capacity. Lactate produced by glycolytic Type II fibers during exercise is a critical fuel substrate for Type I fibers and cardiac muscle [5]. Zone 2 training improves the capacity of oxidative fibers to take up and oxidize lactate via the monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B (LDH-B) system, increasing the lactate threshold and improving the body's overall capacity to manage metabolic by-products of exercise.</p>
<h3>References</h3>
<p>[1] Liang H, Ward WF. PGC-1α: a key regulator of energy metabolism. <em>Adv Physiol Educ</em>. 2006;30:145–151.
[2] Hoppeler H, Flück M. Plasticity of skeletal muscle mitochondria. <em>J Exp Biol</em>. 2003;206:2143–2152.
[3] Spriet LL. New insights into the interaction of carbohydrate and fat metabolism during exercise. <em>Sports Med</em>. 2014;44:87–96.
[4] Hood DA, et al. Maintenance of skeletal muscle mitochondria in health, exercise, and aging. <em>Annu Rev Physiol</em>. 2019;81:19–41.
[5] Brooks GA. The science and translation of lactate shuttle theory. <em>Cell Metab</em>. 2018;27:757–785.</p>
<h2>Practical Programming</h2>
<h3>Identifying Zone 2 Intensity</h3>
<p>Zone 2 is defined physiologically as the intensity corresponding to maximal fat oxidation and lactate steady state—specifically below the first lactate threshold (LT1). In practical terms, Zone 2 can be identified using several methods:</p>
<p><strong>Talk test:</strong> The individual can speak in complete sentences without significant respiratory distress. Any difficulty completing a sentence indicates intensity above Zone 2.</p>
<p><strong>Heart rate:</strong> Approximately 60–70% of maximum heart rate (HRmax) for most individuals. A more precise estimate is 180 minus age as a crude heuristic, though this can vary substantially between individuals.</p>
<p><strong>Lactate testing:</strong> The gold standard is laboratory measurement of blood lactate at various exercise intensities, with LT1 identified as the inflection point where lactate begins to rise above resting levels (typically 1.5–2.0 mmol/L).</p>
<p><strong>Perceived exertion:</strong> <a href="/terms/rate-of-perceived-exertion/" class="term-link" data-slug="rate-of-perceived-exertion" title="RPE">RPE</a> of 3–4 on a 1–10 scale, or "light to moderate" effort—comfortable enough to sustain for 30–60 minutes continuously.</p>
<h3>Volume Recommendations</h3>
<p>Current evidence suggests that the majority of elite endurance athletes perform approximately 80% of their total <a href="/terms/training-volume/" class="term-link" data-slug="training-volume" title="training volume">training volume</a> in Zone 2 (low intensity) and 20% at high intensity—the so-called "polarized" training model [1]. For general health optimization in non-athletes, the target is 150–300 minutes per week of <a href="/terms/zone-2-training/" class="term-link" data-slug="zone-2-training" title="Zone 2 training">Zone 2 training</a>, as consistent with major public health guidelines for moderate-intensity exercise.</p>
<p>For individuals combining Zone 2 training with resistance training, 2–3 sessions per week of 30–60 minutes per session provides the metabolic health and fitness benefits of Zone 2 while minimizing interference with resistance training adaptations [2].</p>
<h3>Modality Selection</h3>
<p>Zone 2 can be performed across any aerobic modality: cycling, walking, running, rowing, elliptical, or swimming. The choice of modality should consider musculoskeletal loading (running imposes higher impact forces than cycling), enjoyment and adherence, and any overlap with lower body resistance training that might contribute to cumulative fatigue.</p>
<h3>Integration with Resistance Training</h3>
<p>For individuals pursuing both <a href="/terms/muscle-hypertrophy/" class="term-link" data-slug="muscle-hypertrophy" title="muscle hypertrophy">muscle hypertrophy</a> and metabolic health, the following scheduling framework minimizes interference:
- Perform Zone 2 sessions on separate days from resistance training where possible
- When same-day training is necessary, resistance training should precede Zone 2
- Keep Zone 2 intensity truly in Zone 2; drifting into Zone 3–4 substantially increases AMPK activation and interference potential [3]</p>
<h3>Adaptation Timeline</h3>
<p>Measurable improvements in fat oxidation and lactate threshold typically emerge within 4–8 weeks of consistent Zone 2 training at adequate volume. Substantial mitochondrial remodeling and cardiovascular adaptations accrue over 3–6 months. Zone 2 training should be viewed as a long-term infrastructure investment in metabolic and cardiovascular health rather than a short-term intervention.</p>
<h3>References</h3>
<p>[1] Seiler S, Kjerland GØ. Quantifying training intensity distribution in elite endurance athletes. <em>Scand J Med Sci Sports</em>. 2006;16:49–56.
[2] Murach KA, Bagley JR. Skeletal muscle hypertrophy with concurrent exercise training. <em>J Strength Cond Res</em>. 2016;30:1991–2004.
[3] Baar K. Using molecular biology to maximize <a href="/terms/concurrent-training/" class="term-link" data-slug="concurrent-training" title="concurrent training">concurrent training</a>. <em>Sports Med</em>. 2014;44:117–125.</p>