FIGURE 8.

Proposed model of β-amyloid mediated muscle dysfunction in IBM. Increased expression of APP and accumulation of its proteolytic Aβ fragments affects numerous intracellular regulatory complexes. Modulation of the intracellular Ca²⁺ release channels (RyR), dihydropyridine receptors (DHPR) and possibly other surface membrane Ca²⁺ channels leads to Ca²⁺ efflux and influx, respectively, which contribute to augmentation of the resting cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i). Aβ accumulation also leads to decreased Ca²⁺ release by RyRs. Augmented [Ca²⁺]_i together with modification of mitochondrial function by Aβ lead to enhanced Ca²⁺ flux into the mitochondrial matrix and subsequent mitochondrial Ca²⁺ overload. Mitochondrial Ca²⁺ overload promotes enhanced generation of ROS, mitochondrial permeability transition pore complex opening, and disruption of ΔΨ_m. Diminished ΔΨ_m results in inefficient TCA cycle and reduction in mitochondrial ATP production. Increased ROS production in combination with acidic cytoplasm promotes lipid peroxidation, further increase in [Ca²⁺]_i, and reduction in Ca²⁺ release from the SR through modulation of the RyRs. All of these events combine to lead to diminished muscle contractility. Solid arrows represent observed, whereas dashed arrows represent unconfirmed effects of Aβ.