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Mitochondria are the primary source of energy production and are implicated in a wide range of biological processes in most eukaryotic cells. Skeletal muscle heavily relies on mitochondria for energy supplements. In addition to being a powerhouse, mitochondria evoke many functions in skeletal muscle, including regulating calcium and reactive oxygen species levels. A healthy mitochondria population is necessary for the preservation of skeletal muscle homeostasis, while mitochondria dysregulation is linked to numerous myopathies. In this review, we summarize the recent studies on mitochondria function and quality control in skeletal muscle, focusing mainly on in vivo studies of rodents and human subjects. With an emphasis on the interplay between mitochondrial functions concerning the muscle fiber type-specific phenotypes, we also discuss the effect of aging and exercise on the remodeling of skeletal muscle and mitochondria properties.

PINK1-Parkin mediated mitophagy, a selective form of autophagy, represents one of the most important mechanisms in mitochondrial quality control (MQC) via the clearance of damaged mitochondria. Although it is well known that the conjugation of mammalian ATG8s (mATG8s) to phosphatidylethanolamine (PE) is a key step in autophagy, its role in mitophagy remains controversial. In this study, we clarify the role of the mATG8-conjugation system in mitophagy by generating knockouts of the mATG8-conjugation machinery. Unexpectedly, we show that mitochondria could still be cleared in the absence of the mATG8-conjugation system, in a process independent of lysosomal degradation. Instead, mitochondria are cleared via extracellular release through a secretory autophagy pathway, in a process we define as Autophagic Secretion of Mitochondria (ASM). Functionally, increased ASM promotes the activation of the innate immune cGAS-STING pathway in recipient cells. Overall, this study reveals ASM as a mechanism in MQC when the cellular mATG8-conjugation machinery is dysfunctional and highlights the critical role of mATG8 lipidation in suppressing inflammatory responses. The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.

Dysregulation of mTOR complex 1 (mTORC1) activity drives neuromuscular junction (NMJ) structural instability during aging; however, downstream targets mediating this effect have not been elucidated. Here, we investigate the roles of two mTORC1 phosphorylation targets for mRNA translation, ribosome protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), in regulating NMJ structural instability induced by aging and sustained mTORC1 activation. While myofiber-specific deletion of S6k1 has no effect on NMJ structural integrity, 4EBP1 activation in murine muscle induces drastic morphological remodeling of the NMJ with enhancement of synaptic transmission. Mechanistically, structural modification of the NMJ is attributed to increased satellite cell activation and enhanced post-synaptic acetylcholine receptor (AChR) turnover upon 4EBP1 activation. Considering that loss of post-synaptic myonuclei and reduced NMJ turnover are features of aging, targeting 4EBP1 activation could induce NMJ renewal by expanding the pool of post-synaptic myonuclei as an alternative intervention to mitigate sarcopenia. The group of Shih-Yin Tsai observed age-associated neuromuscular junction structural instability in male but not female mice which is driven by dysregulation of mTOR complex 1 activity. Genetic activation of the downstream phosphorylation target 4EBP1 in the muscle remodeled the neuromuscular junction and enhanced synaptic transmission.

Background Chronic mTORC1 activation in skeletal muscle is linked with age‐associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E‐binding proteins (4EBPs). Whole‐body knockout of S6K1 or muscle‐specific over‐expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1‐mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1‐mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear. Methods Mice with myofiber‐specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1‐mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt‐TSC1mKO or S6K1‐TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development. Results Here, we show that 4EBP1mt‐TSC1mKO, but not S6K1‐TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P < 0.001) and strength (36.8% increase compared with TSC1mKO, P < 0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two‐fold reduction compared with TSC1mKO, P < 0.05) and restored autophagy flux without relieving mTORC1‐mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5‐fold reduction compared with TSC1mKO, P < 0.05) in muscle and restored mitochondrial homeostasis and function. Conclusions We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia.

Key Points A long-standing paradigm has been that E2F activity is tightly regulated by the RB tumour suppressor and that the disruption of this regulation leads to unscheduled progression through the cell cycle. Based on structure–function studies in vitro , the mammalian E2F family of transcription factors has been artificially subdivided into activators (E2F1–E2F3) and repressors (E2F4–E2F8). E2F1–E2F3 activators are highly redundant during development. Tumour models using RB–E2F compound-mutant mice and E2F-transgenic mice show dual roles for E2Fs in tumour promotion and suppression. These results suggest tissue-specific functions and argue against a uniform role for E2Fs in cancer. Mice lacking E2F1, E2F2 or E2F3 survive to mid gestation without global defects in the cell cycle, suggesting that the activators are not essential for normal mammalian cell proliferation. We propose that under normal conditions E2Fs do not substantially contribute to the proliferative potential of a cell. Deregulated expression or activity of most members of the E2F family has been detected in many human cancers. We propose that the requirement for certain E2F family members in proliferation under oncogenic conditions represents a recent evolutionary adaptation. RB inactivation and E2F amplification coexist in cancer. RB inactivation leads to inappropriate cell cycle progression through the deregulation of E2F function. We propose that the additional increase in E2F activity caused by amplification has cell proliferation-independent functions in cancer. The E2F transcription factors function in cell cycle control and are intimately regulated by RB. However, some tumours have concurrent RB1 inactivation and E2F overexpression. Are there alternative tumour-promoting activities for the E2F family that are independent of cell cycle regulation? Mutations of the retinoblastoma tumour suppressor gene ( RB1 ) or components regulating the RB pathway have been identified in almost every human malignancy. The E2F transcription factors function in cell cycle control and are intimately regulated by RB. Studies of model organisms have revealed conserved functions for E2Fs during development, suggesting that the cancer-related proliferative roles of E2F family members represent a recent evolutionary adaptation. However, given that some human tumours have concurrent RB1 inactivation and E2F amplification and overexpression, we propose that there are alternative tumour-promoting activities for the E2F family, which are independent of cell cycle regulation.

Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.

Deregulation of the Myc pathway and deregulation of the Rb pathway are two of the most common abnormalities in human malignancies. Recent in vitro experiments suggest a complex cross-regulatory relationship between Myc and Rb that is mediated through the control of E2F. To evaluate the functional connection between Myc and E2Fs in vivo, we used a bitransgenic mouse model of Myc-induced T cell lymphomagenesis and analyzed tumor progression in mice deficient for E2f1, E2f2, or E2f3. Whereas the targeted inactivation of E2f1 or E2f3 had no significant effect on tumor progression, loss of E2f2 accelerated lymphomagenesis. Interestingly, loss of a single copy of E2f2 also accelerated tumorigenesis, albeit to a lesser extent, suggesting a haploinsufficient function for this locus. The combined ablation of E2f1 or E2f3, along with E2f2, did not further accelerate tumorigenesis. Myc-overexpressing T cells were more resistant to apoptosis in the absence of E2f2, and the reintroduction of E2F2 into these tumor cells resulted in an increase of apoptosis and inhibition of tumorigenesis. These results identify the E2f2 locus as a tumor suppressor through its ability to modulate apoptosis.

Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity.

E2F proteins: reasons for diversity The E2F family is a family of proteins, some of which act as transcription activators and others as repressors. Here Shih-Yin Tsai et al . tested why there is such genetic complexity by inactivating the entire subset of activators singly or in combination in mice. They show that E2f3a is sufficient to support mouse embryonic and postnatal development. However, expression of E2f3b or E2f1 from the E2f3a locus suppressed all the postnatal phenotypes associated with the inactivation of E2f3a. They conclude there is functional redundancy among activators and that the requirement for E2f3a during postnatal development is dictated by its regulatory sequences, not by its protein function. These findings provide a molecular basis for the observed specificity among E2F activators during development. The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions 1 , 2 . Whereas C. elegans 3 and Drosophila melanogaster 4 , 5 have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins 1 , 2 , 6 . Why such genetic complexity evolved in mammals is not known. To begin to evaluate this genetic complexity, we targeted the inactivation of the entire subset of activators, E2f1 , E2f2 , E2f3a and E2f3b , singly or in combination in mice. We demonstrate that E2f3a is sufficient to support mouse embryonic and postnatal development. Remarkably, expression of E2f3b or E2f1 from the E2f3a locus ( E2f3a 3bki or  E2f3a 1ki , respectively) suppressed all the postnatal phenotypes associated with the inactivation of E2f3a . We conclude that there is significant functional redundancy among activators and that the specific requirement for E2f3a during postnatal development is dictated by regulatory sequences governing its selective spatiotemporal expression and not by its intrinsic protein functions. These findings provide a molecular basis for the observed specificity among E2F activators during development.

Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are infrequent, casting doubt on a direct role for E2Fs in driving cancer. In this work, a mutation analysis of human cancer revealed subtle but impactful copy number gains in E2F1 and E2F3 in hepatocellular carcinoma (HCC). Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output, we have shown that copy number gains in E2f1 or E2f3b resulted in dosage-dependent spontaneous HCC in mice without the involvement of additional organs. Conversely, germ-line loss of E2f1 or E2f3b, but not E2f3a, protected mice against HCC. Combinatorial mapping of chromatin occupancy and transcriptome profiling identified an E2F1- and E2F3B-driven transcriptional program that was associated with development and progression of HCC. These findings demonstrate a direct and cell-autonomous role for E2F activators in human cancer.