bims-askmum 2026-11-08 papers

bims-askmum

Biomed News

on Aging skeletal muscle and mitochondria

Issue of 2026–11–08
nine papers selected by
Victoria Sanfrancesco, York University

Proteostasis network dysregulation in aging skeletal muscle: Mechanisms and therapeutic targets in sarcopenia and muscle wasting.
Targeting Endoplasmic Reticulum Stress as a Promising Strategy Against Aging.
Molecular and signaling mechanisms involved in cellular responses to mitochondrial DNA damage.
Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.
Yeast Mitochondrial Escape 1-Like as a Mitochondrial Gatekeeper in Aging-Related Cardiovascular Disease.
Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.
Branched-chain amino acids in skeletal and cardiac muscles: a review of metabolic variations and cancer's impact.
Revitalizing aging muscles: harnessing NAD⁺, sirtuins, and exercise to combat sarcopenia.
Evidence for spermine oxidase (SMOX) as a regulator of skeletal muscle mass throughout the lifespan.

Exp Gerontol. 2026 Oct 31. pii: S0531-5565(26)00353-0. [Epub ahead of print] 113373

Proteostasis network dysregulation in aging skeletal muscle: Mechanisms and therapeutic targets in sarcopenia and muscle wasting.

Syeda Kubra, Farhad Badshah, Gholamreza Abdi.

  Aging is a universal biological process signified by a time-dependent decline in physiological activity, driven by molecular and cellular damage, leading to greater susceptibility to diseases and fatal outcomes. Impaired proteostasis is a key aspect of cellular aging in which the cells become less efficient at folding, repairing, and recycling proteins, consequently inducing accumulation of damaged and aggregation-prone proteins. The onset of muscle loss is driven by a reduction in protein synthesis, heightened activation of proteolytic pathways, and elevated ER stress factors, collectively contributing to functional decline and increased vulnerability with aging. Muscle atrophy, whether age-related or driven by chronic illness, represents a major role in defective health, impacting both quality of life and survival. This review explores the intricate and multidimensional nature of proteostasis network regulating protein quality control across skeletal muscles. We examined how the malfunction of components within proteostasis networks during aging contributes to the induction, progression, and chronicity of common age-related muscle wasting. Experimental and clinical studies exploring potential therapeutic strategies for better proteostasis in muscle wasting have been discussed. In this review, we emphasized the increasing demand for effective therapeutic interventions that can slow down or mitigate age-related deterioration in muscle physiology and sustain mobility and quality of life in the elderly. We analyzed the roles of ubiquitin proteasome system, autophagy lysosomal pathway, and unfolded protein response in muscle wasting, highlighting protein loss from synthesis-degradation imbalance as a major driver of muscle atrophy under catabolic conditions. This review outlines key findings with emerging insights to help drive the development of targeted therapies against muscle wasting. Looking ahead, emerging approaches such as PROTACs, extracellular vesicle-based therapies, and artificial intelligence-driven predictive models hold promise for advancing precision interventions in muscle wasting research.

Keywords:  Aging; Autophagy lysosome pathway; Muscle wasting; Proteostasis; Sarcopenia; Therapeutics; Ubiquitin proteasome system; Unfolded protein response

DOI:  https://doi.org/10.1016/j.exger.2026.113373
Front Biosci (Landmark Ed). 2026 Oct 10. 31(10): 48989

Targeting Endoplasmic Reticulum Stress as a Promising Strategy Against Aging.

Liuying Hu, Hongyu Li, Dilare Abudurexiti, Mengjie Tian, Hong Wang, Qi Liu, Wangjie Sun, Xiaoxu Zhang, Zhirui Fang, Lu Chen.

  The endoplasmic reticulum (ER) is a vital organelle in eukaryotic cells that plays a key role in processes such as protein folding, post-translational modifications, and the regulation of intracellular calcium storage. Disruptions in ER function as organisms age can lead to endoplasmic reticulum stress (ERS), which activates the unfolded protein response (UPR). The UPR aims to restore ER homeostasis by modulating protein synthesis, facilitating the degradation of misfolded proteins and increasing the expression of molecular chaperones. However, sustained or severe ERS can trigger apoptosis, and has been associated with various age-related pathologies, such as neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. In this review, we systematically explore the pathophysiological mechanisms of ERS and the UPR, with a particular focus on structural and functional alterations during aging. Furthermore, we have summarized the significant roles of ERS and the UPR in various age-related diseases, review recent advances in anti-aging therapies targeting these pathways, and discuss potential future intervention strategies.

Keywords:  aging; apoptosis; endoplasmic reticulum stress; molecular chaperones; unfolded protein response

DOI:  https://doi.org/10.31083/FBL48989
Genet Mol Biol. 2026 ;pii: S1415-47572026000500131. [Epub ahead of print]49Suppl 1(Suppl 1): e20260020

Molecular and signaling mechanisms involved in cellular responses to mitochondrial DNA damage.

Sofia Ligia Guimarães-Ramos, Beatriz Kopel, Felippe Truglio Machado, Laís Yoshie Morikawa Muta, Rebeca Bueno-Alves, Wesley Roger Rodrigues Ferreira, Nadja Cristhina de Souza-Pinto.

Mitochondria are essential organelles in mammalian cells, performing multiple functions ranging from energy metabolism and intracellular signaling to the regulation of cell fate. Proper mitochondrial function depends on the coordinated expression of two distinct genomes: the nuclear genome and the mitochondrial genome, known as mitochondrial DNA (mtDNA). Although most mitochondrial proteins are encoded by nuclear genes, mtDNA encodes 13 polypeptides that are essential components of the oxidative phosphorylation (OXPHOS) system and ATP production. For reasons that are not yet fully understood, mtDNA accumulates DNA damage at levels estimated to be 1-5 times higher than those observed in nuclear DNA, underscoring the importance of efficient DNA repair and damage tolerance mechanisms within mitochondria. Mammalian mitochondria are competent in several DNA repair pathways, with base excision repair being the best characterized. However, the molecular mechanisms underlying DNA damage response (DDR) pathways activated by mtDNA lesions remain poorly defined. In this review, we briefly summarize the established DNA repair pathways operating in mammalian mitochondria, which have been extensively discussed elsewhere, and focus primarily on DDR components implicated in the response to mtDNA damage, as well as on the cellular consequences of mtDNA damage accumulation.

DOI: https://doi.org/10.1590/1678-4685-GMB-2026-0020
Front Aging Neurosci. 2026 ;18 1903701

Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging.

Emilie M Legault, Juan-Pablo Izabal Gamez, Janelle Drouin-Ouellet.

   Introduction: In humans, aging is associated with an increased risk of developing neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). In neurons, the effect of aging on intrinsic molecular processes, and how they tie to age-related neurodegeneration remains unclear. Animal studies have shown that mitochondrial function decline, autophagy impairment and defective elimination of damaged mitochondria by mitophagy are all central features of neuronal aging. However, very few studies have investigated such events in human neurons, due to a lack of models showing aging features. Therefore, there is a crucial need for a better understanding of the effect of aging on neuronal health.
Methods: Here, we use direct neuronal reprogramming, which maintains signatures of cellular aging, to study the effect of aging on mitochondrial health and mitophagy in human neurons derived from healthy donors ranging from 11 to 91 years old. We use confocal imaging to assess colocalization of mitochondria with autophagic structures following mitophagy induction.
Results: We show age-related mitochondrial impairment in neurites of induced neurons (iNs) derived from older donors. Additionally, in these neurites, we show an accumulation of mitochondria targeted for degradation in autophagosomes and LAMP1-positive lysosomal vesicles following mitophagy induction. These impairments culminate into incomplete elimination of damaged mitochondria, despite preserved activity of the lysosomal enzymes assessed.
Conclusion: This study shows for the first time age-related mitophagy impairment in human neurons, and confirms findings of age-related mitochondrial impairments in human neurons. By doing so, this study paves the way for more in-depth mechanistic studies that would allow for the identification of therapeutic targets for anti-aging treatment and in the context of age-associated neurodegenerative diseases.

Keywords:  aging; direct neuronal reprogramming; human neurons; induced neurons; lysosomal function; mitochondria; mitochondrial health; mitophagy

DOI:  https://doi.org/10.3389/fnagi.2026.1903701
Rev Cardiovasc Med. 2026 Oct;27(10): 49477

Yeast Mitochondrial Escape 1-Like as a Mitochondrial Gatekeeper in Aging-Related Cardiovascular Disease.

Zhihao Wan, Xiaorong Li, Xiaoli Zhou, Yongzheng Guo.

  Mitochondrial dysfunction is a hallmark of aging and is closely linked to the progression of cardiovascular disease. Yeast mitochondrial escape 1-like (YME1L) is an adenosine triphosphate (ATP)-dependent i-AAA (intermembrane space AAA, AAA=ATPase associated with diverse cellular activities) protease embedded in the mitochondrial inner membrane that maintains mitochondrial homeostasis by regulating proteostasis, cristae architecture, and metabolic adaptation. Notably, YME1L influences mitochondrial fusion-fission dynamics, respiratory chain supercomplex organization, and oxidative phosphorylation efficiency through the regulated processing of optic atrophy protein 1 (OPA1). Accumulating evidence suggests that age-associated impairment of YME1L function contributes to mitochondrial fragmentation, energetic insufficiency, and reduced stress tolerance, particularly in long-lived, high-energy demand tissues. In the cardiovascular system, experimental models indicate that YME1L deficiency disrupts cristae organization, promotes maladaptive metabolic remodeling, and promotes heart failure-like phenotypes. Conversely, preservation of YME1L activity supports mitochondrial integrity and enhances cardiac resilience under hemodynamic stress. In addition to cardiomyocytes, YME1L also supports endothelial mitochondrial homeostasis, thereby linking mitochondrial proteostasis to vascular aging and diastolic dysfunction. Although YME1L has been extensively studied in cancer biology, its relevance to aging-related cardiovascular vulnerability is increasingly recognized, especially in cardio-oncology, where therapy-induced mitochondrial stress may be exacerbated by age-dependent decline in mitochondrial quality control. This review integrates current evidence supporting YME1L as a context-dependent regulator of mitochondrial stress adaptation, with particular emphasis on the roles of YME1L in cardiovascular aging, heart failure with preserved ejection fraction (HFpEF), and stress tolerance. Rather than positioning YME1L as a universal therapeutic target, we discuss how modulating YME1L-associated pathways may help preserve mitochondrial resilience and mitigate age-related cardiovascular dysfunction.

Keywords:  aging; cardiovascular diseases; heart failure; mitochondria; mitochondrial dynamics; proteostasis

DOI:  https://doi.org/10.31083/RCM49477
Am J Physiol Cell Physiol. 2026 Nov 06.

Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.

Jarrod A Call, Junwon Heo, Edmund R S Kunji, Kelsey H Fisher-Wellman.

  The proton motive force (PMF) across the inner mitochondrial membrane drives ATP synthesis. Biochemistry textbooks give a maximum yield of 30-32 ATP per glucose, but this is a theoretical ceiling, reached only under complete coupling with ATP synthase as the sole consumer of the gradient. No living cell operates there. The PMF is a shared resource, and its allocation among consumers sets the mitochondrion's effective output: the gap between theoretical and effective yield is a reallocation to transport, redox maintenance, and biogenesis. This review re-examines the textbook yield, including the c-ring stoichiometry of ATP synthase, and catalogs the major PMF consumers and their proton costs. The widely quoted figure corresponds to no measured or structurally determined stoichiometry, a mismatch noted previously and consolidated here, and the c-ring subunit count is an upper bound on synthase efficiency under ideal coupling. We assemble these costs into a consolidated proton budget: a range whose upper limit is the ceiling at which the PMF drives ATP synthesis alone. Its lower limit cannot yet be calculated, because the resting flux through most PMF consumers has never been measured; we therefore list every term that this calculation would require and mark those still missing. The result is a framework for reasoning, not a closed set of numbers. Practical consequence: the PMF and membrane potential are composite quantities, so a change in membrane potential should not be read as a change in ATP synthesis, nor the non-phosphorylating residual as passive leak.

Keywords:  P/O ratio; membrane potential; molecule and ion transport; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpcell.90010.2026
Front Physiol. 2026 ;17 1943433

Branched-chain amino acids in skeletal and cardiac muscles: a review of metabolic variations and cancer's impact.

Julian Chrzanowski, Wojciech Graboń, Karolina Buchajska, Agnieszka Cudnoch-Jędrzejewska.

  Branched-chain amino acids (BCAA) - leucine, isoleucine, and valine - serve as essential regulators of energy homeostasis, protein turnover, and nutrient signaling in striated muscle. However, their metabolic processing varies substantially across tissues. This review contrasts BCAA metabolism in skeletal versus cardiac muscle and evaluates how cancer alters it. Skeletal muscle functions as the main site for whole-body BCAA transamination and oxidation, distributing these amino acids between protein synthesis and oxidative catabolism in line with physiological needs. In comparison, the myocardium maintains low baseline BCAA oxidation, depends primarily on fatty acids and glucose, and tightly limits BCAA catabolic flux to prevent the buildup of intermediates that would undermine mitochondrial function. In malignancies, BCAA metabolism is reconfigured in a way that depends on tumor type: many tumors increase BCAA uptake and suppress catabolism in order to preserve intracellular stores, as a result maintaining mechanistic target of rapamycin complex 1 (mTORC1) signaling and supporting proliferation. Using lung, pancreatic and colorectal cancers as main examples, we outline how this tumor-driven metabolic rewiring is linked to cancer cachexia - a multi-organ syndrome in which inflammation, mitochondrial dysfunction, and impaired anabolic signaling promote muscle and cardiac wasting rather than simple substrate limitation. We describe first the mechanisms shared by skeletal and cardiac muscle, then the features specific to each tumor type, and we distinguish throughout between cardiac evidence obtained in tumor-bearing hosts and inferences extrapolated from heart failure. We conclude that interventions directed at BCAA are most reasonable early in the disease course, and only when paired with approaches that suppress inflammation and restore mitochondrial quality control. We also identify priorities for tissue-specific biomarkers and for future research.

Keywords:  BCAA catabolism; branched-chain amino acids; cancer cachexia; cardiac muscle; muscle wasting; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2026.1943433
J Bioenerg Biomembr. 2026 Nov 03. pii: 61. [Epub ahead of print]58(1):

Revitalizing aging muscles: harnessing NAD⁺, sirtuins, and exercise to combat sarcopenia.

Yan Wang, Guimei Zhang.

  Aging is associated with systemic metabolic dysfunction that contributes to geriatric syndromes such as sarcopenia-the progressive loss of skeletal muscle mass and function. Evidence from preclinical models suggests that age-associated depletion of nicotinamide adenine dinucleotide (NAD⁺) may contribute to this decline by limiting the activity of sirtuin deacetylases (SIRT1-7). These enzymes act as metabolic sensors regulating mitochondrial biogenesis, oxidative capacity, DNA repair and pathways related to muscle atrophy. Physical exercise enhances NAD⁺ salvage through upregulation of nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological approaches including NAD⁺ precursor supplementation (nicotinamide riboside or nicotinamide mononucleotide) and inhibition of NAD⁺-consuming enzymes have shown benefits in preclinical models. However, clinical translation remains inconsistent. Recent meta-analyses have found no significant effect of these precursors on muscle mass or strength in adults aged over 60 years. Moreover, experimental evidence indicates that even profound NAD⁺ depletion in adult mouse skeletal muscle does not necessarily compromise function or accelerate aging. We conclude that pharmacological NAD⁺ restoration alone is currently insufficient to reverse sarcopenia in humans. A synergistic approach combining exercise with targeted NAD⁺ support, together with emerging strategies involving precursor transporters, trigonelline and hypothalamic NAD⁺-sirtuin circuits, represents a testable avenue that requires rigorous, stratified clinical evaluation.

Keywords:  Aging; Exercise; NAD⁺ metabolism; Sarcopenia; Sirtuins; Skeletal muscle; Translational gap

DOI:  https://doi.org/10.1007/s10863-026-10140-y
Ageing Res Rev. 2026 Nov 03. pii: S1568-1637(26)00429-0. [Epub ahead of print]123 103437

Evidence for spermine oxidase (SMOX) as a regulator of skeletal muscle mass throughout the lifespan.

Cristhian F Montenegro, Kevin A Murach, Toby L Chambers.

  Age-associated loss of muscle mass and function, termed sarcopenia, increases morbidity and mortality risks concomitant with decreased physical activity. Chronic exercise training is the most effective countermeasure against sarcopenia, but physical limitations create a barrier to participation in the elderly. Investigation into alternative pharmaceutical and nutraceutical treatments to prevent sarcopenia and maintain muscle plasticity late-in-life are therefore warranted. Polyamine metabolism regulates many facets of skeletal muscle biology with the potential for targeted treatments in conditions of compromised muscle health and plasticity. Particularly, spermidine is shown to benefit muscle health in mammalian models of ageing and exercise training. Endogenous production of spermidine is partially regulated by the enzyme spermine oxidase (SMOX). SMOX catabolism cleaves spermine into spermidine to maintain a healthy polyamine pool. Anabolic signaling regulates SMOX expression suggesting a supporting role of polyamines during muscle hypertrophy. SMOX overexpression in skeletal muscle retains muscle fiber size in atrophy-inducing animal models (e.g. immobilization, fasting, denervation) potentially driven by reciprocal downregulation of p21, a marker of cellular senescence. In satellite cells, spermidine improves satellite cell function by restoring autophagy and mitophagy, potentially related to anti-ageing Yamanaka factors. Abundance of SMOX is highest in fast-twitch muscle fiber types but can respond in a fiber-type and exercise dependent manner. In humans, higher basal SMOX expression after strength training correlates to higher strength gains, but investigations of SMOX's actions in humans are lacking. Further defining the role of SMOX in animal and human models will facilitate future skeletal muscle-specific therapeutics to promote youthfulness during ageing.

Keywords:  Ageing; Polyamine metabolism; Skeletal muscle; Spermine oxidase

DOI:  https://doi.org/10.1016/j.arr.2026.103437