# Efzimfotase Alfa Improves Respiratory Capacity in Muscle Tissue From a Mouse Model of HPP

## TL;DR

Efzimfotase alfa, a treatment for HPP, improves muscle mitochondrial function in mice and shows similar issues in human patients.

## Contribution

Shows that efzimfotase alfa improves mitochondrial respiration in HPP mice and reveals altered mitochondrial morphology in human HPP muscle tissue.

## Key findings

- Efzimfotase alfa treatment improved maximal respiration by 147% in HPP mice.
- Efzimfotase alfa increased mitochondrial spare respiratory capacity by 262% in HPP mice.
- Human HPP muscle biopsies showed atypical mitochondrial morphology.

## Abstract

Hypophosphatasia (HPP) is an inherited metabolic disease caused by deficient tissue‐nonspecific alkaline phosphatase (ALP) activity and characterized by skeletal and nonskeletal symptoms, including muscle weakness and fatigue. We hypothesized that mitochondrial respiration is impaired in muscle in HPP, independent of skeletal manifestations, and that the second‐generation ALP enzyme replacement therapy (ERT) efzimfotase alfa improves respiration. Akp2GW−/− mice were used for this purpose. Body weight, bone mineralization, and survival were validated in Akp2GW−/− mice versus Akp2−/− mice, an established model of HPP. No significant differences were found, validating the Akp2GW−/− model. Respiratory outcomes were measured in skeletal muscle fiber bundles in age‐ and sex‐matched Akp2GW−/− and Akp2GW+/+ (wild‐type) mice; bone mineralization was assessed. Mean maximal respiration and mitochondrial spare respiratory capacity (SRC) in vehicle‐treated Akp2GW−/− mice were 37% and 30% of values from wild‐type mice, respectively, independent of skeletal manifestations. Efzimfotase alfa treatment significantly improved maximal respiration in tissue from Akp2GW−/− mice by 147% versus vehicle (p = 0.0059) and improved SRC by 262% versus vehicle (p = 0.0008). Mean maximal respiration and SRC in tissue from efzimfotase alfa‐treated Akp2GW−/− mice were 92% and 107%, respectively, of tissue from wild‐type mice. Cellular ultrastructure of muscle biopsies from people with HPP showed atypical mitochondrial morphology, including branching cristae and dispersed matrix. In a mouse model of HPP, we show that the altered mitochondrial respiration in skeletal muscle is improved by ERT and that HPP is characterized by altered muscle mitochondrial morphology in humans. Together, these data suggest ERT could improve muscular symptoms in HPP.

This article provides evidence for the presence of reduced mitochondrial respiratory capacity in a mouse model of hypophosphatasia (HPP), even in the absence of observable skeletal manifestations.Treatment with a second‐generation enzyme replacement therapy normalizes mitochondrial respiratory capacity in HPP mice.Altered mitochondrial morphology is demonstrated in micrographs of muscle tissue from patients with HPP, corroborating preclinical findings.

This article provides evidence for the presence of reduced mitochondrial respiratory capacity in a mouse model of hypophosphatasia (HPP), even in the absence of observable skeletal manifestations.

Treatment with a second‐generation enzyme replacement therapy normalizes mitochondrial respiratory capacity in HPP mice.

Altered mitochondrial morphology is demonstrated in micrographs of muscle tissue from patients with HPP, corroborating preclinical findings.