Biology subjects

Rebalka, I. A.

Publications and source records attributed to Rebalka, I. A..

2 recordsLinked to original sources

bioRxiv2023

Skeletal Muscle Mitochondrial Morphology Negatively Affected by Loss of Xin

Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins have been reported to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated alterations to mitochondrial structure and function in mice lacking the cytoskeletal adapter protein, Xin. Xin deficient (Xin-/-) and wild-type (WT) littermate mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before high-resolution respirometry, histology, electron microscopy and Western blot analyses of their skeletal muscles were conducted. Immuno-electron microscopy and immunofluorescence staining indicates that Xin is present in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed Xin-/- mice were notably different from WT; frequently spanning a whole sarcomere and/or swollen in appearance with abnormal cristae. Succinate Dehydrogenase and Cytochrome Oxidase IV (COX) activity staining indicated greater evidence of mitochondrial enzyme activity in Xin-/- mice. HFD did not result in a difference between cohorts with respect to body mass gains or glucose handling. However, electron microscopy revealed significantly greater mitochondrial density ([~]2.1-fold) with evident structural abnormalities (swelling, reduced cristae density) in Xin-/- mice. Complex I and II-supported respiration were not different between groups per mg muscle, but when made relative to mitochondrial density, were significantly lower in Xin-/- muscles. Western blotting of fusion, fission, and autophagy proteins revealed no differences between groups. These results provide the first evidence for a role of Xin in maintaining mitochondrial morphology and function but not in regulating mitochondrial dynamics.

cell biology↗

bioRxiv2023

The adiponectin analogue ALY688-SR attenuates diaphragm fibrosis, atrophy and mitochondrial stress in a mouse model of Duchenne muscular dystrophy

Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analogue ALY688-SR prevents fibrosis and fibre type-specific atrophy in diaphragm of D2.mdx mice treated from days 7-28 of age. ALY688-SR also lowered IL-6mRNA but increased IL-6 and TGF-{beta} protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also lowered in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling and force generating properties during the very early stages of disease progression in D2.mdx mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR partially prevents fibrosis and atrophy in the more disease-apparent diaphragm of young D2.mdx mice in relation to lower mitochondrial redox stress. These results provide a foundation for the exploration of slow-release adiponectin-based therapies to prevent fibrosis and atrophy in Duchenne muscular dystrophy.

physiology↗