GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

ISOLATION OF A PERSISTENTLY QUIESCENT MUSCLE SATELLITE CELL POPULATION.

While studies have identified characteristics of quiescent satellite cells, their isolation has been hampered by the fact that the isolation procedures result in the activation of these cells into their rapidly proliferating progeny (myoblasts). Thus, the use of myoblasts for therapeutic (regenerative medicine) or industrial applications (cellular agriculture) has been impeded by the limited proliferative and differentiative capacity of these myogenic progenitors. Here we identify a subpopulation of satellite cells isolated from mouse skeletal muscle using flow cytometry that are highly Pax7-positive, exhibit a very slow proliferation rate (7.7 ± 1.2 days/doubling), and are capable of being maintained in culture for at least three months without a change in phenotype. These cells can be activated from quiescence using a p38 inhibitor or by exposure to freeze-thaw cycles. Once activated, these cells proliferate rapidly (22.7 ± 0.2 hours/doubling), have reduced Pax7 expression (3-fold decrease in Pax7 fluorescence vs. quiescence) and differentiate into myotubes with a high efficiency. Furthermore, these cells withstand freeze-thawing readily without a significant loss of viability (83.1 ± 2.1% live). The results presented here provide researchers with a method to isolate quiescent satellite cells, allowing for more detailed examinations of the factors affecting satellite cell quiescence/activation and providing a cell source that has a unique potential in the regenerative medicine and cellular agriculture fields.

The slow-release adiponectin analog ALY688-SR modifies early-stage disease development in the D2.mdx mouse model of Duchenne muscular dystrophy.

Fibrosis is associated with respiratory and limb muscle atrophy in Duchenne muscular dystrophy (DMD). Current standard of care partially delays the progression of this myopathy but there remains an unmet need to develop additional therapies. Adiponectin receptor agonism has emerged as a possible therapeutic target to lower inflammation and improve metabolism in mdx mouse models of DMD but the degree to which fibrosis and atrophy are prevented remain unknown. Here, we demonstrate that the recently developed slow-release peptidomimetic adiponectin analog, ALY688-SR, remodels the diaphragm of murine model of DMD on DBA background (D2.mdx) mice treated from days 7-28 of age during early stages of disease. ALY688-SR also lowered interleukin-6 (IL-6) mRNA but increased IL-6 and transforming growth factor-ß1 (TGF-ß1) protein contents in diaphragm, suggesting dynamic inflammatory remodeling. ALY688-SR alleviated mitochondrial redox stress by decreasing complex I-stimulated H2O2 emission. Treatment also attenuated fibrosis, fiber type-specific atrophy, and in vitro diaphragm force production in diaphragm suggesting a complex relationship between adiponectin receptor activity, muscle remodeling, and force-generating properties during the very early stages of disease progression in murine model of DMD on DBA background (D2.mdx) mice. In tibialis anterior, the modest fibrosis at this young age was not altered by treatment, and atrophy was not apparent at this young age. These results demonstrate that short-term treatment of ALY688-SR in young D2.mdx mice partially prevents fibrosis and fiber type-specific atrophy and lowers force production in the more disease-apparent diaphragm in relation to lower mitochondrial redox stress and heterogeneous responses in certain inflammatory markers. These diverse muscle responses to adiponectin receptor agonism in early stages of DMD serve as a foundation for further mechanistic investigations.NEW & NOTEWORTHY There are limited therapies for the treatment of Duchenne muscular dystrophy. As fibrosis involves an accumulation of collagen that replaces muscle fibers, antifibrotics may help preserve muscle function. We report that the novel adiponectin receptor agonist ALY688-SR prevents fibrosis in the diaphragm of D2.mdx mice with short-term treatment early in disease progression. These responses were related to altered inflammation and mitochondrial functions and serve as a foundation for the development of this class of therapy.

Discovery-Based Proteomics Identify Skeletal Muscle Mitochondrial Alterations as an Early Metabolic Defect in a Mouse Model of ß-Thalassemia.

Although metabolic complications are common in thalassemia patients, there is still an unmet need to better understand underlying mechanisms. We used unbiased global proteomics to reveal molecular differences between the th3/+ mouse model of thalassemia and wild-type control animals focusing on skeletal muscles at 8 weeks of age. Our data point toward a significantly impaired mitochondrial oxidative phosphorylation. Furthermore, we observed a shift from oxidative fibre types toward more glycolytic fibre types in these animals, which was further supported by larger fibre-type cross-sectional areas in the more oxidative type fibres (type I/type IIa/type IIax hybrid). We also observed an increase in capillary density in th3/+ mice, indicative of a compensatory response. Western blotting for mitochondrial oxidative phosphorylation complex proteins and PCR analysis of mitochondrial genes indicated reduced mitochondrial content in the skeletal muscle but not the hearts of th3/+ mice. The phenotypic manifestation of these alterations was a small but significant reduction in glucose handling capacity. Overall, this study identified many important alterations in the proteome of th3/+ mice, amongst which mitochondrial defects leading to skeletal muscle remodelling and metabolic dysfunction were paramount.

Alterations in skeletal muscle repair in young adults with type 1 diabetes mellitus.

Though preclinical models of type 1 diabetes (T1D) exhibit impaired muscle regeneration, this has yet to be investigated in humans with T1D. Here, we investigated the impact of damaging exercise (eccentric quadriceps contractions) in 18 physically active young adults with and without T1D. Pre- and postexercise (48 h and 96 h), the participants provided blood samples, vastus lateralis biopsies, and performed maximal voluntary quadriceps contractions (MVCs). Skeletal muscle sarcolemmal integrity, extracellular matrix (ECM) content, and satellite cell (SC) content/proliferation were assessed by immunofluorescence. Transmission electron microscopy was used to quantify ultrastructural damage. MVC was comparable between T1D and controls before exercise. Postexercise, MVC was decreased in both groups, but subjects with T1D exhibited moderately lower strength recovery at both 48 h and 96 h. Serum creatine kinase, an indicator of muscle damage, was moderately higher in participants with T1D at rest and exhibited a small elevation 96 h postexercise. Participants with T1D showed lower SC content at all timepoints and demonstrated a moderate delay in SC proliferation after exercise. A greater number of myofibers exhibited sarcolemmal damage (disrupted dystrophin) and increased ECM (laminin) content in participants with T1D despite no differences between groups in ultrastructural damage as assessed by electron microscopy. Finally, transcriptomic analyses revealed dysregulated gene networks involving RNA translation and mitochondrial respiration, providing potential explanations for previous observations of mitochondrial dysfunction in similar cohorts with T1D. Our findings indicate that skeletal muscle in young adults with moderately controlled T1D is altered after damaging exercise, suggesting that longer recovery times following intense exercise may be necessary.

Normal to enhanced intrinsic mitochondrial respiration in skeletal muscle of middle- to older-aged women and men with uncomplicated type 1 diabetes.

AIMS/HYPOTHESIS: This study interrogated mitochondrial respiratory function and content in skeletal muscle biopsies of healthy adults between 30 and 72 years old with and without uncomplicated type 1 diabetes. METHODS: Participants (12 women/nine men) with type 1 diabetes (48 ± 11 years of age), without overt complications, were matched for age, sex, BMI and level of physical activity to participants without diabetes (control participants) (49 ± 12 years of age). Participants underwent a Bergström biopsy of the vastus lateralis to assess mitochondrial respiratory function using high-resolution respirometry and citrate synthase activity. Electron microscopy was used to quantify mitochondrial content and cristae (pixel) density. RESULTS: Mean mitochondrial area density was 27% lower (p = 0.006) in participants with type 1 diabetes compared with control participants. This was largely due to smaller mitochondrial fragments in women with type 1 diabetes (-18%, p = 0.057), as opposed to a decrease in the total number of mitochondrial fragments in men with diabetes (-28%, p = 0.130). Mitochondrial respiratory measures, whether estimated per milligram of tissue (i.e. mass-specific) or normalised to area density (i.e. intrinsic mitochondrial function), differed between cohorts, and demonstrated sexual dimorphism. Mass-specific mitochondrial oxidative phosphorylation (OXPHOS) capacity with the substrates for complex I and complex II (CI + II) was significantly lower (-24%, p = 0.033) in women with type 1 diabetes compared with control participants, whereas mass-specific OXPHOS capacities with substrates for complex I only (pyruvate [CI pyr] or glutamate [CI glu]) or complex II only (succinate [CII succ]) were not different (p > 0.404). No statistical differences (p > 0.397) were found in mass-specific OXPHOS capacity in men with type 1 diabetes compared with control participants despite a 42% non-significant increase in CI glu OXPHOS capacity (p = 0.218). In contrast, intrinsic CI + II OXPHOS capacity was not different in women with type 1 diabetes (+5%, p = 0.378), whereas in men with type 1 diabetes it was 25% higher (p = 0.163) compared with control participants. Men with type 1 diabetes also demonstrated higher intrinsic OXPHOS capacity for CI pyr (+50%, p = 0.159), CI glu (+88%, p = 0.033) and CII succ (+28%, p = 0.123), as well as higher intrinsic respiratory rates with low (more physiological) concentrations of either ADP, pyruvate, glutamate or succinate (p < 0.012). Women with type 1 diabetes had higher (p < 0.003) intrinsic respiratory rates with low concentrations of succinate only. Calculated aerobic fitness (Physical Working Capacity Test [PWC130]) showed a strong relationship with mitochondrial respiratory function and content in the type 1 diabetes cohort. CONCLUSIONS/INTERPRETATION: In middle- to older-aged adults with uncomplicated type 1 diabetes, we conclude that skeletal muscle mitochondria differentially adapt to type 1 diabetes and demonstrate sexual dimorphism. Importantly, these cellular alterations were significantly associated with our metric of aerobic fitness (PWC130) and preceded notable impairments in skeletal mass and strength.

Correction to: Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes.

In Fig. 1e the rate of mitochondrial H2O2 emission was incorrectly shown as being per second rather than per minute.

Sexual dimorphism in human skeletal muscle mitochondrial bioenergetics in response to type 1 diabetes.

Sexual dimorphism in mitochondrial respiratory function has been reported in young women and men without diabetes, which may have important implications for exercise. The purpose of this study was to determine if sexual dimorphism exists in skeletal muscle mitochondrial bioenergetics in people with type 1 diabetes (T1D). A resting muscle microbiopsy was obtained from women and men with T1D (n = 10/8, respectively) and without T1D (control; n = 8/7, respectively). High-resolution respirometry and spectrofluorometry were used to measure mitochondrial respiratory function, hydrogen peroxide (mH2O2) emission and calcium retention capacity (mCRC) in permeabilized myofiber bundles. The impact of T1D on mitochondrial bioenergetics between sexes was interrogated by comparing the change between women and men with T1D relative to the average values of their respective sex-matched controls (i.e., delta). These aforementioned analyses revealed that men with T1D have increased skeletal muscle mitochondrial complex I sensitivity but reduced complex II sensitivity and capacity in comparison to women with T1D. mH2O2 emission was lower in women compared with men with T1D at the level of complex I (succinate driven), whereas mCRC and mitochondrial protein content remained similar between sexes. In conclusion, women and men with T1D exhibit differential responses in skeletal muscle mitochondrial bioenergetics. Although larger cohort studies are certainly required, these early findings nonetheless highlight the importance of considering sex as a variable in the care and treatment of people with T1D (e.g., benefits of different exercise prescriptions).

Alterations in mitochondrial functions and morphology in muscle and non-muscle tissues in type 1 diabetes: implications for metabolic health.

NEW FINDING: What is the topic of this review? Evidence of impaired mitochondrial functions and/or morphology in people with type 1 diabetes across various organ systems. What advances does it highlight? Impairments to mitochondrial functions and morphology may be a primary mechanism underlying the pathophysiology of various complications in people with type 1 diabetes. ABSTRACT: We recently made the observation that there are significant alterations to the ultrastructure and functions of mitochondria in skeletal muscle of people with type 1 diabetes (T1D). These alterations are proposed to lead to decreased energy production in skeletal muscle during exercise and thus may contribute to the impaired aerobic exercise capacity reported in some people with T1D. This Symposium Review summarizes the evidence that similar alterations also occur in the mitochondria present in organ systems outside skeletal muscle in people with T1D, and that this may contribute to the development and progression of the known complications of T1D, which eventually lead to the reported premature mortality.

The impact of statins on physical activity and exercise capacity: an overview of the evidence, mechanisms, and recommendations.

PURPOSE: Statins are among the most widely prescribed medications worldwide. Considered the 'gold-standard' treatment for cardiovascular disease (CVD), statins inhibit HMG-CoA reductase to ultimately reduce serum LDL-cholesterol levels. Unfortunately, the main adverse event of statin use is the development of muscle-associated problems, referred to as SAMS (statin-associated muscle symptoms). While regular moderate physical activity also decreases CVD risk, there is apprehension that physical activity may induce and/or exacerbate SAMS. While much work has gone into identifying the epidemiology of SAMS, only recent research has focused on the extent to which these muscle symptoms are accompanied by functional declines. The purpose of this review is to provide an overview of possible mechanisms underlying SAMS and summarize current evidence regarding the relationship between statin treatment, physical activity, exercise capacity, and SAMS development. METHODS: PubMed and Google Scholar databases were used to search the most relevant and up-to-date peer-reviewed research on the topic. RESULTS: The mechanism(s) behind SAMS, including altered mitochondrial metabolism, reduced coenzyme Q10 levels, reduced vitamin D levels, impaired calcium homeostasis, elevated extracellular glutamate, and genetic polymorphisms, still lack consensus and remain up for debate. Our summation of the evidence leads us to suggest that the etiology of SAMS development is likely multifactorial. Our review also demonstrates that there is limited evidence for statins impairing exercise adaptations or reducing exercise capacity for the majority of the investigated populations. CONCLUSION: The available evidence indicates that the benefits of engaging in physical activity while on statin medication largely outweigh the risks.

The Systemic Effects of Exercise on Regulators of Muscle and Bone in Girls and Women.

PURPOSE: To assess the systemic effects of an acute bout of moderate-intensity exercise on factors that are known to regulate muscle and bone growth in prepubertal girls and women. METHODS: A total of 12 prepubertal girls (8-10 y) and 12 women (20-30 y) cycled at 60% maximal oxygen uptake for 1 hour followed by 1 hour recovery. Blood samples were collected at rest, mid-exercise, end of exercise, mid-recovery, and end of recovery. Plasma was analyzed for interleukin-6, chemokine ligand 1, fibroblast growth factor-2, total insulin growth factor-1 (IGF-1), and free IGF-1 using enzyme-linked immunosorbent assays assays. RESULTS: Both groups had similar concentrations of systemic factors at baseline with the exception of free IGF-1, which was higher in girls (P = .001). Interleukin-6 response was lower in girls versus women (P = .04), with a difference of +105.1% at end of exercise (P < .001), +113.5% at mid-recovery (P = .001), and +93.2% at end of recovery (P = .02). Girls and women exhibited significant declines in chemokine ligand 1, fibroblast growth factor-2, and total IGF-1 during recovery. CONCLUSION: Compared with women, an acute bout of moderate-intensity exercise in girls elicits a lower inflammatory response, suggesting that other mechanisms may be more important for driving the anabolic effects of exercise on muscle and bone in girls.

Statin administration activates system xC- in skeletal muscle: a potential mechanism explaining statin-induced muscle pain.

Statins are a cholesterol-lowering drug class that significantly reduce cardiovascular disease risk. Despite their safety and effectiveness, musculoskeletal side-effects, particularly myalgia, are prominent and the most common reason for discontinuance. The cause of statin-induced myalgia is unknown, so defining the underlying mechanism(s) and potential therapeutic strategies is of clinical importance. Here we tested the hypothesis that statin administration activates skeletal muscle system xC-, a cystine/glutamate antiporter, to increase intracellular cysteine and therefore glutathione synthesis to attenuate statin-induced oxidative stress. Increased system xC- activity would increase interstitial glutamate; an amino acid associated with peripheral nociception. Consistent with our hypothesis, atorvastatin treatment significantly increased mitochondrial reactive oxygen species (ROS; 41%) and glutamate efflux (up to 122%) in C2C12 mouse skeletal muscle myotubes. Statin-induced glutamate efflux was confirmed to be the result of system xC- activation, as cotreatment with sulfasalazine (system xC- inhibitor) negated this rise in extracellular glutamate. These findings were reproduced in primary human myotubes but, consistent with being muscle-specific, were not observed in primary human dermal fibroblasts. To further demonstrate that statin-induced increases in ROS triggered glutamate efflux, C2C12 myotubes were cotreated with atorvastatin and various antioxidants. α-Tocopherol and cysteamine bitartrate reversed the increase in statin-induced glutamate efflux, bringing glutamate levels between 50 and 92% of control-treated levels. N-acetylcysteine (a system xC- substrate) increased glutamate efflux above statin treatment alone: up to 732% greater than control treatment. Taken together, we provide a mechanistic foundation for statin-induced myalgia and offer therapeutic insights to alleviate this particular statin-associated side-effect.

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice.

KEY POINTS: Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia. A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined. Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre-clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia. At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind-like 1 protein from myonuclear foci and improved mRNA alternative splicing. ABSTRACT: Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild-type (SED-WT) mice, as well as sedentary human skeletal actin-long repeat animals, a murine model of DM1 myopathy (SED-DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX-DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70-85% decrease in the duration of myotonic discharges in muscles from EX-DM1 compared to SED-DM1 animals. The exercise-induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle-specific chloride channel (CLC-1) transcripts. CLC-1 protein content and sarcolemmal expression were lower in SED-DM1 versus SED-WT animals, but they were similar between SED-WT and EX-DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG)n foci-positive myonuclei and sequestered Muscleblind-like 1 (MBNL1). Our data indicate that chronic exercise-induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss-of-function, and alternative mRNA splicing.

Considering Type 1 Diabetes as a Form of Accelerated Muscle Aging.

Recent evidence reveals impairments to skeletal muscle health in adolescent/young adults with type 1 diabetes (T1D). Interestingly, the observed changes in T1D are not unlike aged muscle, particularly, the alterations to mitochondria. Thus, we put forth the novel hypothesis that T1D may be considered a condition of accelerated muscle aging and that, similar to aging, mitochondrial dysfunction is a primary contributor to this complication.

Adiponectin-Consideration for its Role in Skeletal Muscle Health.

Adiponectin regulates metabolism through blood glucose control and fatty acid oxidation, partly mediated by downstream effects of adiponectin signaling in skeletal muscle. More recently, skeletal muscle has been identified as a source of adiponectin expression, fueling interest in the role of adiponectin as both a circulating adipokine and a locally expressed paracrine/autocrine factor. In addition to being metabolically responsive, skeletal muscle functional capacity, calcium handling, growth and maintenance, regenerative capacity, and susceptibility to chronic inflammation are all strongly influenced by adiponectin stimulation. Furthermore, physical exercise has clear links to adiponectin expression and circulating concentrations in healthy and diseased populations. Greater physical activity is generally related to higher adiponectin expression while lower adiponectin levels are found in inactive obese, pre-diabetic, and diabetic populations. Exercise training typically restores plasma adiponectin and is associated with improved insulin sensitivity. Thus, the role of adiponectin signaling in skeletal muscle has expanded beyond that of a metabolic regulator to include several aspects of skeletal muscle function and maintenance critical to muscle health, many of which are responsive to, and mediated by, physical exercise.

Loss of the adipokine lipocalin-2 impairs satellite cell activation and skeletal muscle regeneration.

Lipocalin-2 (LCN2) is an adipokine previously described for its contribution to numerous processes, including innate immunity and energy metabolism. LCN2 has also been demonstrated to be an extracellular matrix (ECM) regulator through its association with the ECM protease matrix metalloproteinase-9 (MMP-9). With the global rise in obesity and the associated comorbidities related to increasing adiposity, it is imperative to gain an understanding of the cross talk between adipose tissue and other metabolic tissues, such as skeletal muscle. Given the function of LCN2 on the ECM in other tissues and the importance of matrix remodeling in skeletal muscle regeneration, we examined the localization and expression of LCN2 in uninjured and regenerating wild-type skeletal muscle and assessed the impact of LCN2 deletion (LCN2-/-) on skeletal muscle repair following cardiotoxin injury. Though LCN2 was minimally present in uninjured skeletal muscle, its expression was increased significantly at 1 and 2 days postinjury, with expression present in Pax7-positive satellite cells. Although satellite cell content was unchanged, the ability of quiescent satellite cells to become activated was significantly impaired in LCN2-/- skeletal muscles. Skeletal muscle regeneration was also significantly compromised as evidenced by decreased embryonic myosin heavy chain expression and smaller regenerating myofiber areas. Consistent with a role for LCN2 in MMP-9 regulation, regenerating muscle also displayed a significant increase in fibrosis and lower ( P = 0.07) MMP-9 activity in LCN2-/- mice at 2 days postinjury. These data highlight a novel role for LCN2 in muscle regeneration and suggest that changes in adipokine expression can significantly impact skeletal muscle repair.

Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes.

AIMS/HYPOTHESIS: A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes. METHODS: Physically active, young adults (men and women) with type 1 diabetes (HbA1c 63.0 ± 16.0 mmol/mol [7.9% ± 1.5%]) and without type 1 diabetes (control), matched for sex, age, BMI and level of physical activity, were recruited (n = 12/group) to undergo vastus lateralis muscle microbiopsies. Mitochondrial respiration (high-resolution respirometry), site-specific mitochondrial H2O2 emission and Ca2+ retention capacity (CRC) (spectrofluorometry) were assessed using permeabilised myofibre bundles. Electron microscopy and tomography were used to quantify mitochondrial content and investigate muscle ultrastructure. Skeletal muscle microvasculature was assessed by immunofluorescence. RESULTS: Mitochondrial oxidative capacity was significantly lower in participants with type 1 diabetes vs the control group, specifically at Complex II of the electron transport chain, without differences in mitochondrial content between groups. Muscles of those with type 1 diabetes also exhibited increased mitochondrial H2O2 emission at Complex III and decreased CRC relative to control individuals. Electron tomography revealed an increase in the size and number of autophagic remnants in the muscles of participants with type 1 diabetes. Despite this, levels of the autophagic regulatory protein, phosphorylated AMP-activated protein kinase (p-AMPKαThr172), and its downstream targets, phosphorylated Unc-51 like autophagy activating kinase 1 (p-ULK1Ser555) and p62, was similar between groups. In addition, no differences in muscle capillary density or platelet aggregation were observed between the groups. CONCLUSIONS/INTERPRETATION: Alterations in mitochondrial ultrastructure and bioenergetics are evident within the skeletal muscle of active young adults with type 1 diabetes. It is yet to be elucidated whether more rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.