Near infrared spectroscopy during non-ischaemic handgrip exercise reveals divergent muscle oxygenation signatures in mitochondrial disease and sarcopenia

Background: Mitochondrial dysfunction is a hallmark of ageing and is implicated in the pathogenesis of sarcopenia. Genetically confirmed mitochondrial disease provides a biologically definitive model of impaired oxidative phosphorylation against which novel functional assessments can be validated. We investigated whether a brief, submaximal, non-ischaemic intermittent isometric handgrip exercise protocol combined with Near Infra-Red Spectroscopy (NIRS) could detect distinct muscle oxygenation signatures in mitochondrial disease and sarcopenia. Methods: Adults with genetically confirmed mitochondrial disease (n=10, 7 female) and group-matched controls (n=19, 11 female), underwent assessment of maximal grip force, handgrip relaxation kinetics and a 3-minute intermittent submaximal isometric handgrip test (40% maximal voluntary contraction, 1Hz contraction/relaxation) with continuous force recording at 2000Hz and simultaneous NIRS. Findings were compared with 23 community-dwelling older adults from the Muscle Ageing and Sarcopenia Study (MASS) Lifecourse cohort (n=23, 13 female) including seven with probable or confirmed sarcopenia according to European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Results: Participants with mitochondrial disease demonstrated an attenuated reduction in tissue saturation index (TSI) during exercise compared with controls (TSI % {middle dot} s150-180s: -59.9 {+/-} 94.5 vs -175.1 {+/-} 128.4; p=0.02). Total haemoglobin (THb) responses did not differ between groups (p=0.10). In contrast, participants with probable or confirmed sarcopenia showed exaggerated reduction in TSI compared with non-sarcopenic participants (TSI % {middle dot} s150-180s: -256.5 {+/-} 146.0 vs -121.2 {+/-} 95.2; p=0.05), while THb responses remained similar. The association between sarcopenia and TSI differed by sex (interaction coefficient -240, p=0.016), with greater TSI reductions observed in males with sarcopenia. Differences in TSI between mitochondrial disease and control groups were independent of age and sex. No statistically significant associations were observed between THb responses and age, sex or force production. Conclusions: A brief, non-ischaemic handgrip exercise protocol combined with NIRS identified divergent muscle oxygenation responses in mitochondrial disease and sarcopenia. The attenuated TSI response observed in genetically confirmed mitochondrial disease is consistent with impaired oxygen utilisation secondary to defective oxidative phosphorylation, whereas the exaggerated TSI reduction observed in sarcopenia suggests a distinct physiological mechanism, potentially involving impaired oxygen delivery, reduced muscle efficiency, or both. This portable and non-invasive approach has significant potential as a physiological biomarker for mechanistic studies and clinical trials in ageing and neuromuscular disease. More broadly, our findings demonstrate how biologically defined rare diseases can provide a powerful framework for interpreting mechanisms in common heterogeneous age-related conditions.