Background/Purpose: Muscle weakness and fatigue are frequent manifestations associated with systemic sclerosis (SSc). However, significant gaps remain in our understanding of the effects of SSc on skeletal muscle oxygenation and mitochondrial function. Using a non-invasive approach combining phosphorus- (31P) and proton- (1H) MRS of deoxy-myoglobin (dMb), the purpose of this study was to examine intracellular oxygen (O2) availability, muscle energetics, and mitochondrial function in vivo in the plantar flexor muscles of SSc patients and age-matched healthy controls.

Methods: Six adult with SSc and six healthy controls volunteered to participate in this study after signing a written informed consent. All patients were ANA positive with a SSc-specific antibody with a disease duration of less than 7 years disease duration from first non-Raynaud’s phenomenon. No patients were classified as a myositis overlap. After familiarization, individual WRmax was determined during an incremental dynamic plantar flexion exercise to exhaustion (1 min stages). On a separate day, subjects performed two short bouts of submaximal plantar flexion at ~ 40% of WRmax (frequency of 1 Hz) in the whole-body MR system to assess skeletal muscle mitochondrial function and intracellular oxygenation, respectively. Specifically, after 4 min of data collection at rest, subjects exercised for 4 min followed by 5 min of recovery while 31P-MRS was continuously recorded. After ~20 min of rest, this protocol was repeated using 1H-MRS of deoxy-myoglobin (dMb). At the end of this second protocol, an air-cuff wrapped above the knee was inflated to 250 mmHg for 8 min to achieve complete vascular occlusion and determine the maximum dMb signal. Due to safety concerns, the circulatory occlusion was not completed in one of the SSc patients. All experimental trials were performed in a thermoneutral environment with participants in an overnight fasted state.

Results: Resting concentrations of phosphocreatine, inorganic phosphate, intracellular pH, and adenosine diphosphate in HC and SSc patients are shown in Figure 1. Values are presented as mean ± SD with individual data (n = 6 in both groups). As shown in Figure 2, at rest SSc patients demonstrated significantly lower MbO2 saturation in the calf (SSc: 93 ± 4 % and controls: 99.9 ± 0.3%), although myoglobin-derived O2 consumption and phosphocreatine resynthesis kinetics [PCr] were not significantly different between groups. During the post-exercise recovery period Mb reoxygenation was delayed in patients with SSc as indicated by the significantly lower mean Mb O2 saturation in the calf muscle of SSc patients during the first min of recovery compared with healthy controls (SSc: 83 ± 8 % and controls: 96 ± 3 %). As a result of this limited O2 supply, both the PCr recovery time constant and the peak rate of mitochondrial ATP synthesis (Vmax) were markedly lower in SSc patients than healthy controls (Vmax, SSc: 6.7 ± 4.1 mM·min-1 and 18.4 ± 6.7 mM·min-1) (Figure 3).

Conclusion: These findings suggest that both compromised intracellular O2 availability and impaired mitochondrial oxidative phosphorylation capacity play a central role in the development of muscle weakness and fatigue experienced by SSc patients.

Resting concentrations of phosphocreatine (A), inorganic phosphate (B), intracellular pH (C), and adenosine diphosphate (D) in healthy controls and systemic sclerosis patients. Values are presented as mean ± SD with individual data (n = 6 in both groups).

Resting myoglobin oxygen saturation (left panel) and myoglobin-derived O2 consumption (right panel) in healthy controls and systemic sclerosis patients (A) and Post-exercise myoglobin reoxygenation kinetics (left panel) and the corresponding mean Mb O2 level during the first minute of recovery (right panel) in healthy controls and systemic sclerosis patients (B). Values are presented as mean ± SD with individual data (n = 6 in healthy control; n = 5 in SSc).

Post-exercise phosphocreatine resynthesis kinetics (A) and the corresponding time constant of the monoexponential fit of the individual data (B) in healthy controls and systemic sclerosis patients. Figure 3C displays the estimated peak rate of mitochondrial ATP synthesis in healthy controls and systemic sclerosis patients. Values are presented as mean ± SD with individual data (n = 6 in both groups).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/compromised-intracellular-oxygen-availability-and-severe-mitochondrial-dysfunction-in-the-skeletal-muscle-of-patients-with-systemic-sclerosis/