Dataset Information

Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness.

ABSTRACT: The accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of skeletal muscle aging. Ulk1 is an autophagy-related kinase that initiates autophagosome assembly and may also play a role in autophagosome degradation (i.e., autophagy flux), but the contribution of Ulk1 to healthy muscle aging is unclear. Therefore, the purpose of this study was to investigate the role of Ulk1-mediated autophagy in skeletal muscle aging. At age 22 months (80% survival rate), muscle contractile and metabolic function were assessed using electrophysiology in muscle-specific Ulk1 knockout mice (MKO) and their littermate controls (LM). Specific peak-isometric torque of the ankle dorsiflexors (normalized by tibialis anterior muscle cross-sectional area) and specific force of the fast-twitch extensor digitorum longus muscles was reduced in MKO mice compared to LM mice (p < 0.03). Permeabilized muscle fibers from MKO mice had greater mitochondrial content, yet lower mitochondrial oxygen consumption and greater reactive oxygen species production compared to fibers from LM mice (p ? 0.04). Alterations in neuromuscular junction innervation patterns as well as changes to autophagosome assembly and flux were explored as possible contributors to the pathological features in Ulk1 deficiency. Of primary interest, we found that Ulk1 phosphorylation (activation) to total Ulk1 protein content was reduced in older muscles compared to young muscles from both human and mouse, which may contribute to decreased autophagy flux and an accumulation of dysfunctional mitochondria. Results from this study support the role of Ulk1-mediated autophagy in aging skeletal muscle, reflecting Ulk1's dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.

SUBMITTER: Nichenko AS

PROVIDER: S-EPMC7919824 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness.

Nichenko Anna S AS Sorensen Jacob R JR Southern W Michael WM Qualls Anita E AE Schifino Albino G AG McFaline-Figueroa Jennifer J Blum Jamie E JE Tehrani Kayvan F KF Yin Hang H Mortensen Luke J LJ Thalacker-Mercer Anna E AE Greising Sarah M SM Call Jarrod A JA

International journal of molecular sciences 20210216 4

The accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of skeletal muscle aging. Ulk1 is an autophagy-related kinase that initiates autophagosome assembly and may also play a role in autophagosome degradation (i.e., autophagy flux), but the contribution of Ulk1 to healthy muscle aging is unclear. Therefore, the purpose of this study was to investigate the role of Ulk1-mediated autophagy in skeletal muscle aging. At age 22 months (80% sur ...[more]

PMID: 33669246

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Project description:BackgroundSurgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting.MethodsTo determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5-75) undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3, and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic).ResultsTen patients lost more than 10% of the cross-sectional area of the rectus femoris (RFCSA ) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery (q < 0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q < 0.05). Weighted genome co-expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function (r = -0.72, p = 6 × 10-4 with RFCSA on Day 0, P = 3 × 10-4 with RFCSA on Day 7 and r = -0.73, P = 5 × 10-4 with hand-grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non-wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 P = 0.043 and Day 7 P = 0.016). Wasting patients also showed a greater increase in circulating nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan® showed that pre-surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF-15) (r = 0.79, P = 2 × 10-4 ) and that GDF-15, interleukin (IL)-8), C-C motif chemokine 23 (CCL-23), and IL-15 receptor subunit alpha (IL-15RA) contributed to metabolic changes in response to surgery.ConclusionsWe show that pre-existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction.

Dataset Information

Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness.

Publications

Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness.

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