Dataset Information

Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength.

ABSTRACT: Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

SUBMITTER: Xu Z

PROVIDER: S-EPMC8850466 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength.

Xu Zhisheng Z Fu Tingting T Guo Qiqi Q Zhou Danxia D Sun Wanping W Zhou Zheng Z Chen Xinyi X Zhang Jingzi J Liu Lin L Xiao Liwei L Yin Yujing Y Jia Yuhuan Y Pang Erkai E Chen Yuncong Y Pan Xin X Fang Lei L Zhu Min-Sheng MS Fei Wenyong W Lu Bin B Gan Zhenji Z

Nature communications 20220216 1

Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related m ...[more]

PMID: 35173176

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Project description:BackgroundChronic kidney disease (CKD) is commonly associated with multifactorial neuromuscular impairments. Few studies have investigated CKD-induced changes in maximal voluntary force (MVF), and even fewer have longitudinal follow-up. The aim of this study is to investigate whether CKD progression modifies the relationship between skeletal muscle mass and force, and the prevalence of sarcopaenia and sarcopenic obesity.MethodsThe data used were prospectively collected during routine check-ups in a network of nutritional centres in Mexico and retrospectively analysed. From a dataset of 5430 patients, we selected 1098 patients with available anthropometric, kidney function, handgrip and bioimpedance data. The relationship between appendicular skeletal muscle mass (ASM) and MVF was investigated using mixed models and adjusted for age, sex, body mass index, physical activity level and CKD aetiology. Sarcopaenia prevalence were tested across period of follow-up using the Cochran-Mantel-Haenzen for repeated measures and across CKD stages using the Chi-2 test.ResultsAfter normalization with ASM, MVF was higher in CKD G1-G3 compared with G4 and G5 (P ≤ .001, Cohen's d = 0.270-0.576). Slopes between MVF and ASM were lower in CKD G3, G4 and G5 than in CKD G1-G2 [-2.268 (-3.927, -0.609), P = .008; -2.694 (-4.593, -0.794), P = .006; -3.675 (-5.326, -1.725), P < .001, respectively]. The prevalence of sarcopaenia and sarcopaenic obesity did not differ across CKD stages, but recovery was most commonly observed in CKD G1-G2. Slope analysis showed an independent interaction between the slopes of kidney function and ASM on MVF evolution over time.ConclusionsCKD negatively, progressively and independently affects the neuromuscular system, and force production is reduced for any given muscle mass as CKD progresses. While no association was found between CKD stage and prevalence of sarcopaenia, recovery was more frequent in the early CKD stages. These results suggest the importance of early rehabilitation programs to improve musculoskeletal health, quality of life and survival in CKD patients.

Project description:We aimed to quantify declines from baseline in lower limb skeletal muscle size and strength of uninjured adults following single-leg disuse. We searched EMBASE, Medline, CINAHL, and CCRCT up to 30 January 2022. Studies were included in the systematic review if they (1) recruited uninjured participants; (2) were an original experimental study; (3) employed a single-leg disuse model; and (4) reported muscle strength, size, or power data following a period of single-leg disuse for at least one group without a countermeasure. Studies were excluded if they (1) did not meet all inclusion criteria; (2) were not in English; (3) reported previously published muscle strength, size, or power data; or (4) could not be sourced from two different libraries, repeated online searches, and the authors. We used the Cochrane Risk of Bias Assessment Tool to assess risk of bias. We then performed random-effects meta-analyses on studies reporting measures of leg extension strength and extensor size. Our search revealed 6548 studies, and 86 were included in our systematic review. Data from 35 and 20 studies were then included in the meta-analyses for measures of leg extensor strength and size, respectively (40 different studies). No meta-analysis for muscle power was performed due to insufficient homogenous data. Effect sizes (Hedges' gav ) with 95% confidence intervals for leg extensor strength were all durations = -0.80 [-0.92, -0.68] (n = 429 participants; n = 68 aged 40 years or older; n ≥ 78 females); ≤7 days of disuse = -0.57 [-0.75, -0.40] (n = 151); >7 days and ≤14 days = -0.93 [-1.12, -0.74] (n = 206); and >14 days = -0.95 [-1.20, -0.70] (n = 72). Effect sizes for measures of leg extensor size were all durations = -0.41 [-0.51, -0.31] (n = 233; n = 32 aged 40 years or older; n ≥ 42 females); ≤7 days = -0.26 [-0.36, -0.16] (n = 84); >7 days and ≤14 days = -0.49 [-0.67, -0.30] (n = 102); and >14 days = -0.52 [-0.74, -0.30] (n = 47). Decreases in leg extensor strength (cast: -0.94 [-1.30, -0.59] (n = 73); brace: -0.90 [-1.18, -0.63] (n = 106)) and size (cast: -0.61[-0.87, -0.35] (n = 41); brace: (-0.48 [-1.04, 0.07] (n = 41)) following 14 days of disuse did not differ for cast and brace disuse models. Single-leg disuse in adults resulted in a decline in leg extensor strength and size that reached a nadir beyond 14 days. Bracing and casting led to similar declines in leg extensor strength and size following 14 days of disuse. Studies including females and males and adults over 40 years of age are lacking.

Dataset Information

Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength.

Publications

Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength.

Similar Datasets

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