Compromised muscle energetics and intracellular O2 availability during dynamic contraction in the plantar flexor muscles of patients with systemic sclerosis.

The fundamental intracellular mechanisms underlying exercise intolerance and muscle weakness in patients with systemic sclerosis (SSc) are poorly understood. Thus, in six SSc patients (55 ± 11 yr) and six age-matched healthy controls (50 ± 13 yr), we assessed both skeletal muscle metabolism and intracellular O2 availability in vivo during submaximal contractions. Specifically, during dynamic plantar flexion exercise at 40% of maximal aerobic power, we used a multimodal approach combining phosphorus (31P) and proton (1H) MRS of deoxymyoglobin to examine both skeletal muscle energy pathways and intracellular partial pressure of O2 (iPO2). Both myoglobin O2 levels (SSc: 70 ± 7% and controls: 79 ± 4%; P = 0.03;) and end-exercise iPO2 (SSc: 8 ± 4 mmHg and controls: 17 ± 8 mmHg; P = 0.021; d = 1.36) were lower in SSc than healthy controls. The rate of ATP synthesis from oxidative phosphorylation was also lower in SSc than controls (SSc: 5.2 ± 3.4 mM min-1 and controls: 11.8 ± 3.6 mM min-1;P = 0.015) whereas PCr depletion was augmented (SSc: 55 ± 15% from resting baseline and controls: 77 ± 9% from resting baseline; P = 0.015). This shift toward a greater reliance on anaerobic metabolism led to an accumulation of inorganic phosphate diprotonated during exercise (SSc: 2.7 ± 1.2 mM and controls: 1.4 ± 0.5 mM; P = 0.037). Together, these findings indicate that critically low iPO2 severely limits oxidative phosphorylation rate even during moderate-intensity dynamic plantar flexion exercise in patients with SSc. The magnitude of the disease-induced shift in metabolism and iPO2 was so extensive that it was greater than the metabolic alterations found in patients suffering from advanced chronic cardiovascular diseases. In addition, the compensatory increase in anaerobic metabolism promoted the accumulation of inorganic phosphate diprotonated, which could amplify the susceptibility to muscle fatigue and mediate premature exercise cessation in patients with SSc.