Rahman Fasih A, Graham Mackenzie Q, Truong Alex, Quadrilatero Joe
Department of Kinesiology and Health Sciences, University of Waterloo, 200 University Ave. West, Waterloo, ON, N2L 3G1, Canada.
J Biomed Sci. 2025 Aug 19;32(1):77. doi: 10.1186/s12929-025-01153-7.
Postnatal skeletal muscle development leads to increased muscle mass, strength, and mitochondrial function, but the role of mitochondrial remodeling during this period is unclear. This study investigates mitochondrial remodeling during postnatal muscle development and examines how constitutive autophagy deficiency impacts these processes.
We initially performed a broad RNA-Seq analysis using a publicly available GEO database of skeletal muscle from postnatal day 7 (P7) to postnatal day 112 (P112) to identify differentially expressed genes. This was followed by investigation of postnatal skeletal muscle development using the mitophagy report mouse line (mt-Kiema mice), as well as conditional skeletal muscle knockout (Atg7) mice.
Our study observed rapid growth of body and skeletal muscle mass, along with increased fiber cross-sectional area and grip strength. Mitochondrial maturation was indicated by enhanced maximal respiration, reduced electron leak, and elevated mitophagic flux, as well as increased mitochondrial localization of autophagy and mitophagy proteins. Anabolic signaling was also upregulated, coinciding with increased mitophagy and fusion signaling, and decreased biogenesis signaling. Despite the loss of mitophagic flux in skeletal muscle-specific Atg7 knockout mice, there were no changes in body or skeletal muscle mass; however, hypertrophy was observed in type IIX fibers. This lack of Atg7 and loss of mitophagy was associated with the activation of mitochondrial apoptotic signaling as well as ubiquitin-proteasome signaling, suggesting a shift in degradation mechanisms. Inhibition of the ubiquitin-proteasome system (UPS) in autophagy-deficient skeletal muscle led to significant atrophy, increased reactive oxygen species production, and mitochondrial apoptotic signaling.
These results highlight the role of mitophagy in postnatal skeletal muscle development and suggest that autophagy-deficiency triggers compensatory degradative pathways (i.e., UPS) to prevent mitochondrial apoptotic signaling and thus preserve skeletal muscle integrity in developing mice.
出生后骨骼肌发育会导致肌肉量增加、力量增强以及线粒体功能提升，但在此期间线粒体重塑的作用尚不清楚。本研究调查出生后肌肉发育过程中的线粒体重塑，并探讨组成型自噬缺陷如何影响这些过程。
我们最初使用公开的基因表达综合数据库（GEO数据库）对出生后第7天（P7）至出生后第112天（P112）的骨骼肌进行广泛的RNA测序分析，以鉴定差异表达基因。随后，使用线粒体自噬报告小鼠品系（mt-Kiema小鼠）以及条件性骨骼肌敲除（Atg7）小鼠研究出生后骨骼肌发育情况。
我们的研究观察到身体和骨骼肌质量快速增长，同时纤维横截面积和握力增加。线粒体成熟表现为最大呼吸增强、电子泄漏减少、线粒体自噬通量升高，以及自噬和线粒体自噬蛋白的线粒体定位增加。合成代谢信号也上调，同时线粒体自噬和融合信号增加，生物合成信号减少。尽管骨骼肌特异性Atg7敲除小鼠的线粒体自噬通量丧失，但身体或骨骼肌质量没有变化；然而，在IIX型纤维中观察到肥大。Atg7的缺失和线粒体自噬的丧失与线粒体凋亡信号以及泛素-蛋白酶体信号的激活有关，表明降解机制发生了转变。在自噬缺陷的骨骼肌中抑制泛素-蛋白酶体系统（UPS）会导致显著萎缩、活性氧产生增加以及线粒体凋亡信号。
这些结果突出了线粒体自噬在出生后骨骼肌发育中的作用，并表明自噬缺陷会触发代偿性降解途径（即UPS）以防止线粒体凋亡信号，从而在发育中的小鼠中维持骨骼肌完整性。
