Markers of clinical and mitochondrial adaptation in response to moderate intensity continuous training: A systematic review and meta-analysis

BACKGROUND: Aerobic exercise promotes mitochondrial morphological, enzymatic, and bioenergetic adaptions to improve muscle health and function. Although moderate intensity continuous training (MICT) is frequently recommended for sedentary and multiple clinical populations, there is little consensus regarding the effects of chronic MICT on these adaptations. The aim of this systematic review and meta-analysis is to evaluate the evidence for the effects of MICT on molecular transducers of mitochondrial biogenesis and cardiorespiratory fitness in adults. METHODS: A comprehensive search was conducted in PubMed and CINAHL. Eligible studies assessed MICT lasting ≥2 weeks in adults, published since 2010, and collected vastus lateralis skeletal muscle biopsies pre and post chronic endurance exercise exposure. Data were extracted for mitochondrial transcription factor A (TFAM), citrate synthase (CS), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), mitofusin 2 (MFN2), dynamin-related protein 1 (DRP1), VO₂max, and mitochondrial density (MitoVD). Meta-analyses using inverse-variance random effects models were conducted for outcomes reported in at least three studies. RESULTS: A total of fourteen studies (n = 184) met inclusion criteria, with an overall low to moderate risk of bias and very low to low certainty of evidence. MICT significantly increased MitoVD (p < 0.00001) and VO₂max (p < 0.0001), while CS (p = 0.05) and MFN2 showed a modest increase (p = 0.01) following MICT. No changes were observed for TFAM, DRP1, or PGC-1α. CONCLUSION: MICT significantly improves MFN2 expression, CS activity, MitoVD, and VO2 max in adults. However, the overall quality of evidence is low. Heterogeneity in molecular responses suggests potential moderating effects of training duration, modality (e.g., cycling vs. treadmill), and sex - warranting further research. REGISTRATION: PROSPERO ID:CRD42024611640.