Faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart related to cytosolic inorganic phosphate (Pi) accumulation

Abstract

A model of the cell bioenergetic system was used to compare the effect of oxidative phosphorylation (OXPHOS) deficiencies in a broad range of moderate ATP demand in skeletal muscle and heart. Computer simulations revealed that kinetic properties of the system are similar in both cases despite the much higher mitochondria content and "basic" OXPHOS activity in heart than in skeletal muscle, because of a much higher each-step activation (ESA) of OXPHOS in skeletal muscle than in heart. Large OXPHOS deficiencies lead in both tissues to a significant decrease in oxygen consumption (V̇o2) and phosphocreatine (PCr) and increase in cytosolic ADP, Pi, and H(+) The main difference between skeletal muscle and heart is a much higher cytosolic Pi concentration in healthy tissue and much higher cytosolic Pi accumulation (level) at low OXPHOS activities in the former, caused by a higher PCr level in healthy tissue (and higher total phosphate pool) and smaller Pi redistribution between cytosol and mitochondria at OXPHOS deficiency. This difference does not depend on ATP demand in a broad range. A much greater Pi increase and PCr decrease during rest-to-moderate work transition in skeletal muscle at OXPHOS deficiencies than at normal OXPHOS activity significantly slows down the V̇o2 on-kinetics. Because high cytosolic Pi concentrations cause fatigue in skeletal muscle and can compromise force generation in skeletal muscle and heart, this system property can contribute to the faster and stronger manifestation of mitochondrial diseases in skeletal muscle than in heart. Shortly, skeletal muscle with large OXPHOS deficiencies becomes fatigued already during low/moderate exercise.

Keywords: OXPHOS deficiency; heart; inorganic phosphate; mitochondrial disease; skeletal muscle; tissue specificity.

Fig. 1.

Simulated dependence of V̇o₂ and metabolite concentrations on OXPHOS activity in intact skeletal muscle at moderate ATP demand. A: dependence of V̇o₂, cytosolic ADP and pH, and mitochondrial NADH. B: dependence of cytosolic PCr, ATP, and P_i.

Fig. 2.

Simulated dependence of V̇o₂ and metabolite concentrations on OXPHOS activity in intact heart at moderate ATP demand. A: dependence of V̇o₂, cytosolic ADP and pH, and mitochondrial NADH. B: dependence of cytosolic PCr, ATP, and P_i.

Fig. 3.

Simulated changes in time of V̇o₂, metabolite concentrations and pH, and ATP supply/usage fluxes during rest-to-moderate exercise (ATP demand) transition in skeletal muscle for 100 and 20% of normal OXPHOS activity. Exercise starts at the second minute of simulation. Top: time courses of V̇o₂, cytosolic ADP and pH, and mitochondrial NADH. Middle: time courses of cytosolic PCr, ATP, and P_i. Bottom: ATP usage (vUT), ATP supply by OXPHOS (vOX), ATP supply by CK (vCK), and anaerobic glycolysis (vGL).

Fig. 4.

Simulated changes in time of V̇o₂, metabolite concentrations and pH, and ATP supply/usage fluxes during low-to-medium work (ATP demand) transition in heart for 100 and 20% of normal OXPHOS activity. The work transition starts at the second minute of simulation. Top: time courses of V̇o₂, cytosolic ADP and pH, and mitochondrial NADH. Middle: time courses of cytosolic PCr, ATP, and P_i. Bottom: ATP usage (vUT), ATP supply by OXPHOS (vOX), ATP supply by CK (vCK), and anaerobic glycolysis (vGL).

Fig. 5.

Simulated relationship between t_1/2 for V̇o₂ and percent of normal OXPHOS activity in skeletal muscle.

Fig. 6.

Schematic presentation of the postulated reasons of the difference in cytosolic P_i level at high OXPHOS deficiencies between skeletal muscle and heart and its role for different mitochondrial diseases manifestation in these tissues. In skeletal muscle, a much higher cytosolic P_i and higher PCr (both related to higher total phosphate pool) at normal OXPHOS activity as well as little P_i redistribution between cytosol and mitochondria (that occupy ∼7% of cell volume) lead to a high cytosolic P_i level at OXPHOS deficiency that compromises power generation by actomyosin-ATPase. In heart, a much lower cytosolic P_i and lower PCr at normal OXPHOS activity as well as pronounced P_i redistribution between cytosol and mitochondria (that occupy ∼23% of cell volume) lead to a moderate cytosolic P_i level at OXPHOS deficiency that does not compromise power generation by actomyosin-ATPase. Here, cyt, cytosolic compartment; mit, mitochondrial compartment.