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Loss of skeletal muscle p62 attenuates muscle atrophy in the streptozotocin-induced model of type 1 diabetes in mice
Abstract   Peer reviewed

Loss of skeletal muscle p62 attenuates muscle atrophy in the streptozotocin-induced model of type 1 diabetes in mice

Mitsuharu Okutsu, Mami Yamada, Eiji Warabi, Hisashi Oishi and Vitor A Lira
Physiology (Bethesda, Md.), Vol.41(S1), 2301142
05/2026
DOI: 10.1152/physiol.2026.41.S1.2301142

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Abstract

Abstract only Type 1 diabetes induces skeletal muscle atrophy, which further impairs glucose metabolism, restricts physical activity, and ultimately leads to a deterioration in quality of life. Sequestosome 1/SQSTM1/p62 (p62) is involved in autophagy, positively regulates antioxidant proteins, and blunts inflammatory signaling, thereby contributing to skeletal muscle homeostasis. However, a potential role for p62 in the regulation of muscle wasting in type 1 diabetes remains to be determined. In this study, using a streptozotocin (STZ)-induced mouse model of type 1 diabetes, we demonstrate that STZ injection increases total p62 protein as well as the phosphorylation levels of p62 at Ser351 and Ser401 in skeletal muscle by 31%, 109% and 30%, respectively, suggesting its active involvement in the related muscle phenotype. Muscle-specific p62 knockout (p62 skmKO) mice attenuated STZ-induced muscle atrophy in predominantly glycolytic muscles, including the gastrocnemius (GA), tibialis anterior (TA), and extensor digitorum longus (EDL). STZ injection did not alter protein levels related to ubiquitination, mTOR signaling, antioxidant proteins, inflammatory pathways, or mitochondrial content in EDL muscle, but it did enhance autophagic flux, which was blunted in p62 skmKO mice. In contrast, overexpression of p62 in muscle-specific p62 transgenic mice (p62 mTg) increased autophagic flux in the EDL muscle without aggravating muscle atrophy following STZ administration when compared to wild-type mice. These results suggest that p62 is required for STZ-induced muscle atrophy, likely via autophagy, but not sufficient to enhance autophagic contribution to muscle atrophy in the same context. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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