Skeletal muscle mitochondrial function cannot be properly inferred from PCr resynthesis without taking pH changes into account
Résumé
We have read with much interest the paper recently 9 published by Khushu et al. regarding the impaired muscle 10 metabolism in hypothyroid patients [1]. Although the results 11 of this investigation are of potential interest, we are actually 12 concerned about the utilization of the phosphocreatine 13 recovery rate constant (kPCr) as a simple index of 14 mitochondrial function and the corresponding conclusions 15 regarding the impact of hypothyroidism on muscle metab-16 olism during exercise. The real issue is actually to clearly 17 determine whether one can infer about mitochondrial 18 function on the basis of PCr rate constants measurements. 19 During recovery from exercise, PCr is resynthesized 20 purely as a consequence of oxidative adenosine triphosphate 21 (ATP) synthesis [2], and measurements of the kPCr have 22 been used in order to characterize mitochondrial function in a 23 variety of conditions [3]. However, several studies have 24 clearly demonstrated that cytosolic pH has a strong influence 25 [3]. It is actually well acknowledged that kPCr is inversely 26 related to the extent of intracellular acidosis and PCr 27 consumed [3]. In other words, a significant intracellular 28 acidosis and a large PCr consumption in exercising muscle 29 would be associated with a slower PCr resynthesis [3]. In the 30 Khushu et al. study, cytosolic pH was found to be 31 significantly lower after a 6-min constant-load plantar 32 flexion exercise in hypothyroid patients compared to 33 controls (6.95±0.02 vs. 7.02±0.06, respectively). Therefore, 34 the conclusions of an altered mitochondrial function in 35 hypothyroid patients [1] on the single basis of kPCr 36 measurements have to be interpreted cautiously. Of note, 37 several kinetic parameters are commonly used to describe 38 PCr changes during exercise-to-recovery transition, includ-39 ing kPCr, the initial rate of PCr recovery (ViPCr) and the 40 maximum aerobic capacity (Qmax) [4]. These three 41 parameters characterizing PCr resynthesis are correlated to 42 oxidative capacity. However, in contrast to kPCr, ViPCr and 43 Qmax are insensitive to exercise intensity and end-of-44 exercise metabolic conditions [3]. On that basis, ViPCr and 45 Qmax should be considered as additional indices to compare 46 the postexercise PCr recovery rate and mitochondrial 47 oxidative capacity across different populations when end-48 of-exercise pH and PCr concentration values are different or 49 not taken into account. These additional parameters were 50 considered in some previously published studies which 51 investigated in vivo mitochondrial function from childhood 52 to young and/or late adulthood [5,6]. In contrast, these 53 parameters were not taken into account in other studies 54 which investigated age-related changes in mitochondrial 55 oxidative capacity from childhood to adulthood [7] and 56 examined the association between mitochondrial alterations 57 and insulin sensitivity in overweight and normal-weight 58 children [8]. In the Khushu et al. study, the Qmax calculation 59 was oversimplified as the product of kPCr and the resting 60 [PCr], as previously described [9]. This oversimplification is 61 actually derived from the calculation of the ViPCr from an 62 exponential fitting. In that case, ViPCr is represented by the 63 product of kPCr and the amount of PCr consumed at the end 64 of exercise. On that basis, a few authors have calculated 65 Qmax similarly to ViPCr, with the amount of PCr consumed 66 being replaced by the resting [PCr]. Although mathemati-67 cally plausible, this calculation is not supported by any 68 control model, and the corresponding Qmax is devoid of any 69 enzymatic meaning, as it is the case for the calculation of 70 Qmax using ADP within a Michaelis–Menten framework. 71 This method is then largely questionable because it ignores 72 the commonly accepted theory considering adenosine 73 diphosphate as a key regulator of oxidative ATP synthesis 74 [10]. In addition, with such an approximate calculation, 75 Qmax becomes strongly dependent on kPCr and/or [PCr] 76 measured at rest. In their study, Khushu et al. [1] reported no 77 significant difference in the resting [PCr] values between 78 hypothyroid patients and controls (43.6±0.8 vs. 42.0± 79 1.0 mmol kg −1 , respectively). Given that the resting [PCr] 80 values were similar, the corresponding calculated Qmax 81 values were lower in hypothyroid patients than in controls on 82 the single basis of lower kPCr measurements in hypothyroid 83 patients. Consequently, this result should be interpreted 84 with caution. 85 Overall, it is of utmost importance to keep in mind that 86 one cannot simply infer on mitochondrial function on the 87 basis of measurements of the rate constant of PCr resyn-88 thesis given that end-of-exercise conditions have been 89 shown to exert a strong influence. Future studies should 90 then pay attention to these methodological inaccuracies 91 which might hedge data interpretation and confound the 92 corresponding conclusions.
Domaines
Physiologie [q-bio.TO]
Origine : Fichiers produits par l'(les) auteur(s)