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. 2019 Dec;60(6):769-778.
doi: 10.1002/mus.26702. Epub 2019 Oct 23.

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation

Pieter A Leermakers  1 , Anita E M Kneppers  1 , Annemie M W J Schols  1 , Marco C J M Kelders  1 , Chiel C de Theije  1 , Lex B Verdijk  2 , Luc J C van Loon  2 , Ramon C J Langen  1 , Harry R Gosker  1
Affiliations

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation

Pieter A Leermakers et al. Muscle Nerve. 2019 Dec.

Abstract

Introduction: Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading.

Methods: We analyzed a comprehensive set of molecular markers involved in mitochondrial-autophagy, -biogenesis, -dynamics, and -content, in the gastrocnemius muscle of C57BL/6J mice subjected to 0- and 3-days hind limb suspension, and in biopsies from human vastus lateralis muscle obtained before and after 7 days of one-leg immobilization.

Results: In both mice and men, short-term skeletal muscle unloading results in molecular marker patterns indicative of increased receptor-mediated mitophagy and decreased mitochondrial biogenesis regulation, before apparent loss of mitochondrial content.

Discussion: These results emphasize the early-onset of skeletal muscle disuse-induced mitochondrial remodeling.

Keywords: inactivity; mitochondria; mitochondrial biogenesis; mitophagy; muscle unloading; skeletal muscle.

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Conflict of interest statement

None of the authors has any conflict of interest to disclose.

Figures

Figure 1
Figure 1
HLS‐induced body composition changes in mice. Body weight (A) and muscle weights of hind limb muscles (B) are depicted of the murine study. Statistical significance between indicated bars *P < .05, **P < .01, ***P < .001, or compared with PF && P < .01 are depicted
Figure 2
Figure 2
Mitochondrial quantity in response to muscle UL in murine gastrocnemius and human vastus lateralis muscle. Murine gastrocnemius muscle mitochondrial content‐associated protein levels (A) and enzyme activity (C) are depicted. Human vastus lateralis muscle ΔUL‐BL values of mitochondrial content‐associated protein levels are depicted (B). No statistical significance was found between indicated bars (A,C) or between ΔUL‐BL (B)
Figure 3
Figure 3
Mitophagy‐associated protein and mRNA‐expression in response to muscle UL in murine gastrocnemius and human vastus lateralis muscle. Murine gastrocnemius muscle mitophagy‐associated mRNA‐expression (A) and protein (C) levels are depicted. Human vastus lateralis muscle ΔUL‐BL values of mitophagy‐associated mRNA‐expression (B) and protein (D) levels are depicted. Statistical significance is indicated between indicated bars (A,C) or between ΔUL‐BL (B,D) *P < .05, **P < .01, ***P < .001
Figure 4
Figure 4
Autophagy‐associated protein and mRNA‐expression in response to muscle UL in murine gastrocnemius and human vastus lateralis muscle. Murine gastrocnemius muscle autophagy‐associated mRNA‐expression (A) and protein (C) levels are depicted. Human vastus lateralis muscle ΔUL‐BL values of autophagy‐associated mRNA‐expression (B) and protein (D) levels are depicted. Statistical significance is indicated between indicated bars (A,C) or between ΔUL‐BL (B,D) *P < .05, **P < .01, ***P < .001
Figure 5
Figure 5
Mitochondrial biogenesis‐associated protein and mRNA‐expression in response to muscle UL in murine gastrocnemius and human vastus lateralis muscle. Murine gastrocnemius muscle mitochondrial biogenesis‐associated mRNA‐expression (A) and protein (C) levels are depicted. Human vastus lateralis muscle ΔUL‐BL values mitochondrial biogenesis‐associated mRNA‐expression (B) and protein (D) levels are depicted. Murine gastrocnemius (E) and human vastus lateralis muscle (F) ΔUL‐BL values of nuclear‐ and mitochondrial‐encoded mRNA‐expression of mitochondrial oxidative complexes are depicted. Statistical significance is indicated between indicated bars (A,C,E) or between ΔUL‐BL (B,D,F) *P < .05, **P < .01, ***P < .001
Figure 6
Figure 6
Mitochondrial dynamics‐associated protein and mRNA‐expression in response to muscle UL in murine gastrocnemius and human vastus lateralis muscle. Murine gastrocnemius muscle mitochondrial dynamics‐associated mRNA‐expression (A) and protein (C) levels are depicted. Human vastus lateralis muscle ΔUL‐BL values of mitochondrial dynamics‐associated mRNA‐expression (B) and protein levels (D) are depicted. No statistical significance was found between indicated bars (A,C) or between ΔUL‐BL (B,D)
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