PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity

ABSTRACT

Skeletal muscles play key roles in movement, posture, thermogenesis, and whole-body metabolism. Autophagy plays essential roles in the regulation of muscle mass, function and integrity. However, the molecular machinery that regulates autophagy is still incompletely understood. In our recent study, we identified and characterized a novel Forkhead Box O (FoxO)-dependent gene, PHAF1/MYTHO (phagophore assembly factor 1/macro-autophagy and youth optimizer), as a novel autophagy regulator that controls muscle integrity. MYTHO/PHAF1 is upregulated in multiple conditions leading to muscle atrophy, and downregulation of its expression spares muscle atrophy triggered by fasting, denervation, cachexia and sepsis. Overexpression of PHAF1/MYTHO is sufficient to induce muscle atrophy. Prolonged downregulation of PHAF1/MYTHO causes a severe myopathic phenotype, which is characterized by impaired autophagy, muscle weakness, myofiber degeneration, mammalian target of rapamycin complex 1 (mTORC1) hyperactivation and extensive ultrastructural defects, such as accumulation of proteinaceous and membranous structures and tubular aggregates. This myopathic phenotype is attenuated upon administration of the mTORC1 inhibitor rapamycin. These findings position PHAF1/MYTHO as a novel regulator of skeletal muscle autophagy and tissue integrity.

KEYWORDS:

• Myopathy
• autophagy
• mTOR
• FoxO
• myotonic dystrophy type 1
• muscle atrophy

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by AFM-Telethon (22982), Foundation Leducq, AIRC (17388), AIRC (23257), H2020-MSCA-RISE-2014 project no 645648 ‘Muscle Stress Relief’, ASI (MARS-PRE), CARIPARO, Next Generation EU in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: “Ageing Well in an Ageing Society”. This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022] to MS. This work was also supported by the Natural Sciences and Engineering Council of Canada (NSERC, RGPIN-2021-03724) and Canadian Institutes of Health Research (CIHR) grants (GER-417022, MOV-399334 and MOV-438450). GG is supported by a Chercheur-boursier Junior 2 salary award from the Fonds de recherche du Québec en santé (FRQS-297877). JPLG was supported by a Postdoctoral Fellowship from the FRQS.