FoxO‐dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension
Open accessAbstract
Key points: Muscle atrophy is a debilitating condition that affects a high percentage of the population with a negative impact on quality of life. Dissecting the molecular level of the atrophy process, and the similarities/dissimilarities among different catabolic conditions, is a necessary step for designing specific countermeasures to attenuate/prevent muscle loss. The FoxO family transcription factors represent one of the most important regulators of atrophy programme stimulating the expression of many atrophy‐related genes. The findings of the present study clearly indicate that the signalling network controlling the atrophy programme is specific for each catabolic condition. Muscle atrophy is a complex process that is in common with many different catabolic diseases including disuse/inactivity and ageing. The signalling pathways that control the atrophy programme in the different disuse/inactivity conditions have not yet been completely dissected. The inhibition of FoxO is considered to only partially spare muscle mass after denervation. The present study aimed: (i) to determine the involvement of FoxOs in hindlimb suspension disuse model; (ii) to define whether the molecular events of protein breakdown are shared among different unloaded muscles; and finally (iii) to compare the data obtained in this model with another model of inactivity such as denervation. Both wild‐type and muscle‐specific FoxO1,3,4 knockout (FoxO1,3,4 −/− ) mice were unloaded for 3 and 14 days and muscles were characterized by functional, morphological, biochemical and molecular assays. The data obtained show that FoxOs are required for muscle loss and force drop during unloading. Moreover, we found that FoxO‐dependent atrogenes vary in different unloaded muscles and that they diverge from denervation. The findings of the present study clearly indicate that the signalling network that controls the atrophy programme is specific for each catabolic condition.
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Each catabolic condition differs in muscle susceptibility to atrophy and induction of an atrophy program, and within the same catabolic situation different muscles activate peculiar atrophy-related programs.
“Therefore, each catabolic condition differs from the others in terms of muscle susceptibility to atrophy as well as induction of an atrophy program and within the same catabolic situation, different muscles activate peculiar atrophy-related programs3.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [3]
Skeletal muscles are heterogeneous with respect to fiber type and metabolic properties and vary, often drastically, in their response to the same stimulus.
“First, skeletal muscles are heterogeneous with respect to fiber type and metabolic properties and therefore they vary, often drastically, in their response to the same stimulus.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [3]
During disuse such as that induced by hind limb suspension, the soleus atrophies faster than glycolytic (fast) muscles.
“For instance, slow muscles, such as the soleus, are less sensitive to starvation compared to fast muscles2, while during disuse such as that induced by hind limb suspension, the soleus atrophies faster than glycolytic (fast) muscles3.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [3]
The atrophy program diverges within fast muscles during the same catabolic condition.
“Importantly, the atrophy program diverges within the fast muscles during the same catabolic condition3.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [3]
FoxO1,3,4 are transcription factors downstream of the IGF1/insulin-Akt pathway, and their inhibition completely spares muscle loss and force drop in fasting, hind limb suspension, immobilization, diabetes, and glucocorticoids treatment.
“FoxO1,3,4 are transcription factors downstream the IGF1/insulin-Akt pathway (Fig. 1) and their inhibition completely spares muscle loss and force drop in fasting, hind limb suspension, immobilization, diabetes, and glucocorticoids treatment3,57,63,64.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [3]
Muscle-specific inhibition of FoxOs protects from cancer cachexia-, fasting-, hindlimb suspension- or denervation-induced atrophy.
“Muscle-specific inhibition of FoxOs protects from cancer cachexia-, fasting-, hindlimb suspension- or denervation-induced atrophy [16–18].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [18]
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- Authors
- Brocca, L., Toniolo, L., Reggiani, C., Bottinelli, R., Sandri, M., & Pellegrino, M. A.
- Affiliations
- University of Pavia (IT)
- University of Padua (IT)
- Corresponding author
- Pellegrino, Maria Antonietta
- ORCID
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2016-12-12
- Volume
- 595
- Issue
- 4
- Pages
- 1143-1158
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC5309360
- OpenAlex
- W2532453905
- Cited by
- 93
- References
- 35
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 14 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 1
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- European Commission (22 3576)
- Seventh Framework Programme
- Agenzia Spaziale Italiana (I/044/11/0)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Health Sciences › Medicine › Physiology › Spaceflight effects on biology
- Keywords
- muscle atrophy, FOXO transcription factors, atrogenes, hindlimb unloading, disuse, denervation, protein degradation, muscle unloading, muscle force loss, catabolic conditions, aging
- MeSH terms
- Animals, Muscular Atrophy, Muscle Fibers, Skeletal, Hindlimb Suspension, Mice, Forkhead Transcription Factors
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