Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism
Benedict Abdon, Yusheng Liang, Débora da Luz Scheffer, Mauricio Torres, Neha Shrestha, Rachel B. Reinert, You Lu, Brent Pederson, Amara Bugarin-Lapuz, Sander Kersten, Ling Qi
Benedict Abdon, Yusheng Liang, Débora da Luz Scheffer, Mauricio Torres, Neha Shrestha, Rachel B. Reinert, You Lu, Brent Pederson, Amara Bugarin-Lapuz, Sander Kersten, Ling Qi
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Research Article Cell biology Muscle biology

Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism

Abstract

The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beigeing of adipocytes, and resistance to diet-induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.

Authors

Benedict Abdon, Yusheng Liang, Débora da Luz Scheffer, Mauricio Torres, Neha Shrestha, Rachel B. Reinert, You Lu, Brent Pederson, Amara Bugarin-Lapuz, Sander Kersten, Ling Qi

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Figure 5

SEL1L is required to maintain muscle ER homeostasis.

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SEL1L is required to maintain muscle ER homeostasis. (A) Representative ...
(A) Representative confocal image of tibialis anterior muscle cross section stained for sarcolemma marker dystrophin and ER chaperone BiP. White arrows, perinuclear ER; asterisks, intermyofibrillar ER (n = 3 mice per genotype). (B) Representative confocal image of isolated EDL myofiber stained with ER marker KDEL (n = 5 mice per genotype). White arrows indicate perinuclear ER. (C) Western blot analysis and quantitation (D and E) of ER homeostasis proteins in 4- and 12-week-old muscle (n = 3 mice per genotype/time point). (D) Quantitation of C in 4- and 12-week-old muscle. (E) Quantitation of integrated stress response regulators from C: PERK, p-eIF2α relative to total eIF2α, and ATF4. (F) RT-qPCR of Ire1α, Perk, and BiP in WT and Sel1LMLC quadriceps muscle (n = 5–6 mice per genotype). (G) RT-qPCR analysis of Xbp1 in quadriceps muscle normalized to L32. “u” and “s” represent unspliced and spliced forms, respectively (n = 6 mice per genotype). (H) Western blot of PERK in λ-phosphatase–treated (λPPase-treated) muscle lysates of Sel1Lfl/fl and Sel1LMLC mice. Livers from tunicamycin-treated (1 mg/kg i.p.) mice served as positive control (n = 2 mice per treatment). Data presented as mean ± SEM. NS, P > 0.05; *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 determined by 2-way ANOVA with Dunnett’s multiple-comparison test (D and E), or 2-tailed, unpaired t test (F and G).