Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss
Zhen Jin1,2, Yan Mao1, Qiqi Guo1
1Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing University, Nanjing, China.
Research (Washington, D.C.)
|September 2, 2024
Summary
Microgravity induces mitochondrial protein buildup in skeletal muscle, impairing bone health. This links muscle mitochondrial proteostasis to bone metabolism via FGF21, impacting osteoporosis research.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Microgravity is linked to osteoporosis, but the molecular mechanisms are unclear.
- Skeletal muscle plays a role in bone health, but the underlying pathways are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism linking microgravity, skeletal muscle, and bone loss.
- To investigate the role of mitochondrial proteostasis in skeletal muscle and its impact on bone metabolism.
Main Methods:
- Utilized mouse models with targeted deletion of LONP1 in skeletal muscle.
- Examined the effects of overexpressing a LONP1-degraded protein (ΔOTC) in skeletal muscle.
- Investigated the mitochondrial unfolded protein response (UPRmt) and myokine expression.
- Assessed serum FGF21 levels and their association with bone health in humans.
Main Results:
- Disruptions in skeletal muscle mitochondrial proteolysis (LONP1 deficiency or ΔOTC overexpression) led to reduced bone mass and compromised mechanical function.
- Mitochondrial proteostasis imbalance triggered UPRmt in muscle, up-regulating FGF21.
- FGF21 was identified as a pro-osteoclastogenic factor contributing to bone loss.
- Muscle-bone crosstalk occurred independently of ATF4 in skeletal muscle.
- Serum FGF21 levels were significantly associated with bone health in humans.
Conclusions:
- Skeletal muscle mitochondrial proteostasis is crucial for maintaining bone health.
- UPRmt in muscle, mediated by FGF21, influences bone metabolism.
- This pathway provides a novel link between muscle adaptation to loading conditions and systemic bone regulation.
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