Protein kinase ROCK1 activates mitochondrial fission linking to oxidative stress and muscle atrophy

Chronic kidney disease (CKD) is associated with protein-energy wasting, characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of muscle wasting, underlying mechanisms remain unclear.

Here, we used transcriptomic analysis, metabolomics analyses, and mouse gene manipulation to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting the subtotal nephrectomy mouse models of CKD. The mice with CKD were age- and sex-matched to sham-operated controls.

Through these approaches, Rho-associated kinase ROCK1 emerged as a key molecule responsible for the observed mitochondrial fission and oxidative stress. Specifically, our results showed that the expression of oxidative stress response genes increased, and that of oxidative phosphorylation genes decreased in the muscles of mice with CKD. This was accompanied by reduced oxygen consumption rates, decreased levels of mitochondrial electron transport chain proteins, and increased cellular oxidative damage. Excessive mitochondrial fission was also observed, and we found that the activation of ROCK1 was responsible for this process. Inducible expression of muscle-specific constitutively active ROCK1 exacerbated mitochondrial fragmentation and muscle wasting in CKD mice. Conversely, ROCK1 depletion (ROCK1^-/-) alleviated these phenomena. Mechanistically, ROCK1 activation promoted the recruitment of dynamin-related protein 1 to mitochondria, thereby facilitating mitochondrial fission. Notably, pharmacological inhibition of ROCK1 mitigated muscle wasting by suppressing mitochondrial fission and oxidative stress.

Our findings demonstrate that ROCK1 participates in CKD-induced muscle wasting by promoting mitochondrial fission and oxidative stress. Pharmacological suppression of ROCK1 could be a therapeutic strategy for combating muscle wasting in CKD conditions.