ABSTRACT
The response of skeletal muscle to unaccustomed eccentric exercise has been studied widely, yet it is incompletely understood. This review is intended to provide an up‐to‐date overview of ...our understanding of how skeletal muscle responds to eccentric actions, with particular emphasis on the underlying molecular and cellular mechanisms of damage and recovery. This review begins by addressing the question of whether eccentric actions result in physical damage to muscle fibers and/or connective tissue. We next review the symptomatic manifestations of eccentric exercise (i.e., indirect damage markers, such as delayed onset muscle soreness), with emphasis on their relatively poorly understood molecular underpinnings. We then highlight factors that potentially modify the muscle damage response following eccentric exercise. Finally, we explore the utility of using eccentric training to improve muscle function in populations of healthy and aging individuals, as well as those living with neuromuscular disorders. Muscle Nerve 49: 155–170, 2014
Background: Dynamin-related protein-1 (DRP1) mediates mitochondrial fission. C57 mice with DRP1 knockdown in skeletal muscle (DRP1 KO mice) are resistant to high-fat diet-induced weight gain and ...diabetes, and exhibit reduced adipose tissue. Methods: To explore the mechanisms of diabetes resistance in DRP1 KO mice, we conducted a hyperinsulinemic euglycemic clamp, with glucose clamped at 150 mg/dL. Results: DRP1 KO mice had a glucose infusion rate ranging from 29.9 to 44.4 mg/kg/min over 120 min whereas the rate ranged between 4.6 and 6.3 mg/kg/min in wildtype mice. In previous studies, we found that gene expression of ATF-4, a transcription factor associated with endoplasmic reticulum (ER) stress activation, was elevated in DRP KO mice. Furthermore, gene and protein expression of FGF21 and GDF15, which are downstream signals associated with activation of ER-stress, were also elevated. Conclusions: Down-regulation of DRP1 in skeletal muscle in mice fed a high-fat diet is associated with resistance to diabetes and increased insulin sensitivity measured by hyperinsulinemic euglycemic clamp. This phenotype seems to be mediated through activation of ER-stress response.
Skeletal muscle NKA preferentially utilises ATP derived from glycogenolytic and glycolytic origins, therefore the aim of this study was to determine whether digoxin effects on muscle NKA would reduce ...systemic lactate Lac- with intense exercise and exacerbate fatigue in healthy humans. During FF, plasma Lac-a and Lac-v increased at fatigue compared to rest (P<0.001); Lac-a-v became more negative during each exercise bout (EB) to fatigue (P<0.001); Lac-a-v (corrected for corresponding ∆PVa-v) decreased below rest, indicating a net Lac- entry into plasma during each EB (P<0.001); Lac- flux became more negative (i.e. flux into plasma) during each EB (P<0.001; fatigue, ~157-fold). DIG induced compensatory NKA upregulation was likely in skeletal muscle NKA (data not presented here), thus the observed small DIG effects on plasma lactate during exercise are not surprising.
Background: Frequently interrupting sitting time improves metabolic health outcomes. Recent studies suggest these benefits may be more pronounced than those elicited by a calorie-matched ...single-continuous bout of physical activity (PA) as traditionally prescribed. We aimed to compare skeletal muscle (SkM) mitochondrial respiration and molecular adaptations to short-term exposure to breaks vs energy-matched single continuous bout of PA in adults with overweight to obesity. Methods: Adults (9M/10F, age 32 ± 6 yr, BMI 30 ± 3 kg/m2) completed 3 interventions of a randomized cross-over study: 1) MICRO: hourly 5-min walking bout for 9 hr/d (45-min/d), 2) ONE: 45-min/d single continuous walking bout, 3) SIT: sitting control. Each intervention was 4 days in length (3 days in free-living followed by 24 hr in the lab). On the morning of day 5 (7:30 AM), a fasted SkM biopsy was collected to determine mitochondrial respiratory states in permeabilized SkM fibers by high resolution respirometry, and differentially expressed genes (RNA seq) identified common pathways. Results: Mitochondrial coupling (State3/State4) in the presence of lipid-associated substrates was improved after ONE (4.8 ± 2.5) compared to both SED (2.3 ± 1.0, P = 0.001) and MICRO (3.1 ± 1.1, P = 0.02). In pathways for SkM contraction-transcription signaling, both ONE and MICRO enhanced enrichment (P < 0.0001 for both) and activation of Oxidative Phosphorylation (Z-score > 4, for both) and Sirtuin Signaling (Z-score < -2, for both) pathways was observed. AMPK, mTOR and Ca++ Signaling were enriched in ONE (P < 0.001) vs MICRO (n/s). Conclusions: At same energy expenditure, transcriptional pathways and the mitochondrial ability for fat oxidation were more pronounced in SkM after 4 days of PA performed as a daily single-continuous bout relative to multiple short bouts spread throughout the day. A dose-response in pathway enrichment was present in favor of ONE vs MICRO. Future studies need to test if observed differences translate into improved metabolic health outcomes.
Background: Dynamin Related Protein-1 (DRP1) constricts outer mitochondrial membrane during fission. Notably, skeletal muscles of type 2 diabetics exhibit mitochondrial dysfunction associated with ...increased mitochondrial fragmentation suggesting activation of DRP1.Methods: In this study we explored the phenotype of aging C57 mice (80 weeks-old) with reduced expression of DRP1 in skeletal muscle (KO mice).Results: DRP1 deficiency in male and female aging mice resulted in a reduction in total and fat mass. Male KO mice exhibited elevated plasma GDF15 and FGF21, and reduced insulinemia. Male KO mice exhibited higher energy expenditure, better glucose tolerance but unaltered hypoglycemic response to exogenous insulin as compared to wild type mice. Male KO mice had reduced grip strength of forelimbs but no changes on distance walked on treadmill. We did not observe changes in O2 consumption in isolated skeletal muscle fibers from male KO mice in response to diverse substrates.Conclusions: Our study shows that the depletion of DRP1 in skeletal muscle is associated with increases in plasma GDF15 and FGF21 suggesting activation of endoplasmic reticulum stress response, which could explain higher energy expenditure, better glucose tolerance and resistance to fat accumulation in aging C57 mice. Our results also indicate that DRP1 KO in skeletal muscle impairs maximal force generation during forelimb grip test suggesting skeletal muscle remodeling.
•Cellular senescence drives age-related decline of the musculoskeletal system.•The Senescence Associated Secretory Phenotype (SASP) can chronically impair stem cell function.•The SASP can attenuate ...tissue regeneration in muscle, bone and cartilage during aging.•The SASP disturbs the balance between bone formation and resorption.•Senescence elimination counters musculoskeletal pathologies and frailty in mice.
Aging is the prime risk factor for the broad-based development of diseases. Frailty is a phenotypical hallmark of aging and is often used to assess whether the predicted benefits of a therapy outweigh the risks for older patients. Senescent cells form as a consequence of unresolved molecular damage and persistently secrete molecules that can impair tissue function. Recent evidence shows senescent cells can chronically interfere with stem cell function and drive aging of the musculoskeletal system. In addition, targeted apoptosis of senescent cells can restore tissue homeostasis in aged animals. Thus, targeting cellular senescence provides new therapeutic opportunities for the intervention of frailty-associated pathologies and could have pleiotropic health benefits.
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