Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring...

Area of Science:

• Cellular Biology
• Physiology
• Metabolic Regulation

Background:

• Mammalian target of rapamycin complex 1 (mTORC1) is crucial for regulating cell, organ, and body size.
• Skeletal muscle-specific mTORC1 inactivation in mice leads to smaller fibers, reduced mitochondria, increased glycogen, and fatal myopathy.
• mTORC1 deficiency down-regulates peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), impacting mitochondrial biogenesis and glucose homeostasis.

Purpose of the Study:

• To investigate if enhancing mitochondrial biogenesis can reverse the phenotype in mTORC1-deficient mice.
• To determine the role of PGC-1α induction in mitigating muscle defects caused by mTORC1 inactivation.
• To elucidate the mechanisms underlying glycogen accumulation and myopathy in the absence of mTORC1 signaling.

Main Methods:

• Pharmacological induction of mitochondrial biogenesis.
• Overexpression of PGC-1α in mice.
• Analysis of mitochondrial function, gene expression, and glycogen content.
• Assessment of PKB/Akt signaling pathway activation.

Main Results:

• Both pharmacological and PGC-1α-mediated induction of mitochondrial biogenesis normalized mitochondrial function and gene expression.
• These interventions did not prevent or delay the progressive, lethal myopathy.
• mTORC1 deficiency significantly impacted muscle glycogen content, mediated by PKB/Akt activation affecting both synthesis and degradation.
• Mitochondrial dysfunction, while present, was not the direct cause of the lethal myopathy.

Conclusions:

• Mitochondrial dysfunction in mTORC1-inactivated muscles is primarily due to PGC-1α down-regulation.
• Restoring mitochondrial function alone is insufficient to prevent the fatal myopathy.
• PKB/Akt pathway activation plays a critical role in glycogen dysregulation, independent of mitochondrial impairment, contributing to the myopathy.