Mark Tarnopolsky

McMaster University | McMaster · Division of Neuromuscular & Neurometabolics

Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins have been reported to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated alterations to mitochondrial structure and function in mice lacking the cytoskeletal...

Background: Despite the growing recognition of the obesity crisis, its rates continue to rise. The current first-line therapies, such as dietary changes, energy restriction, and physical activity, are typically met with poor adherence. Novel nutritional interventions can address the root causes of obesity, including mitochondrial dysfunction, and...

Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae...

The study objective is to evaluate the influence of attrition from a paediatric weight management program (PWM) on health indicators over a 2-year period. In this observational study, children and youth with obesity were recruited at entry into a family-based behaviour modification PWM and had four research study visits, independent of clinic visit...

Objective: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studi...

The age‐related loss of skeletal muscle mass and functionality, known as sarcopenia, is a critical risk factor for morbidity and all‐cause mortality. Resistance exercise training (RET) is the primary countermeasure to fight sarcopenia and ageing. Altered intercellular communication is a hallmark of ageing, which is not well elucidated. Circulating...

The Western diet (WD) predisposes to bodyweight gain and obesity and is linked to mitochondrial dysfunction, oxidative damage, inflammation, and multisystem disease, even affecting the reproductive organs, fertility, and pregnancy outcomes. In this study, we investigated the effects of multi-ingredient supplementation (MIS) with antioxidants, phyto...

Radiation exposure is an undeniable health threat encountered in various occupations and procedures. High energy waves in ionizing radiation cause DNA damage and induce reactive oxygen species (ROS) production, which further exacerbate DNA, protein, and lipid damage, increasing risk of mutations. Although endogenous antioxidants such as superoxide...

CAG-expanded ATXN7 has been previously defined in the pathogenesis of spinocerebellar ataxia type 7 (SCA7), a polyglutamine expansion autosomal dominant cerebellar ataxia. Pathology in SCA7 occurs as a result of a CAG triplet repeat expansion in excess of 37 in the first exon of ATXN7 , which encodes ataxin-7. SCA7 presents clinically with spinocer...

Purpose of review: Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies. Recent findings: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/ox...

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integr...

The macroscopic and microscopic deterioration of human skin with age is, in part, attributed to a functional decline in mitochondrial health. We previously demonstrated that exercise attenuated age-associated changes within the skin through enhanced mitochondrial health via IL-15 signaling, an exercise-induced cytokine whose presence increases in c...

Background: Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardio-respiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of phys...

High aerobic endurance capacity can be acquired by training and/or inherited. Aerobic exercise training (AET) and aging are linked to altered gut microbiome composition, but it is unknown if the environmental stress of exercise and host genetics that predispose for higher exercise capacity have similar effects on the gut microbiome during aging. We...

Background: Impaired cough results in airway secretion retention, atelectasis and pneumonia in individuals with Duchenne muscular dystrophy (DMD). Lung volume recruitment (LVR) stacks breaths to inflate the lungs to greater volumes than spontaneous effort. LVR is recommended in DMD clinical care guidelines but is not well studied. We aimed to dete...

Evidence suggests that caffeine (CF) reduces cardiovascular disease (CVD) risk. However, the mechanism by which this occurs has not yet been uncovered. Here, we investigated the effect of CF on the expression of two bona fide regulators of circulating low-density lipoprotein cholesterol (LDLc) levels; the proprotein convertase subtilisin/kexin type...

COVID‐19 (SARS‐CoV‐2 infection) can lead to intensive care unit (ICU) admission and critical illness myopathy (CIM). We examined three ICU patients with COVID‐19, who required mechanical ventilation for pneumonia and developed CIM. Pathological examination of skeletal muscle biopsies revealed myopathic changes consistent with CIM, variable inflamma...

Purpose: To investigate exosome-like vesicle (ELV) plasma concentrations and markers of multivesicular body (MVB) biogenesis in skeletal muscle in response to acute exercise. Methods: Seventeen healthy (BMI: 23.5±0.5kg·m-2) and fifteen prediabetic (BMI: 27.3±1.2kg·m-2) men were randomly assigned to two groups performing an acute cycling bout in...

Whole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or...

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...

We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocati...

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 eighteen physically-active young adults with and without T1D. Pre- and post-exercise (48h and 96h), participants prov...

Background: Spastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). Objective: To study genetic and clinical characteristics of SPG4 across Canada. Methods: The SPAST gene was analyzed in a total of 696 HSP patients fr...

Context: Previous investigations on skeletal muscle health in type 1 diabetes (T1D) has generally focused on later stages of disease progression where comorbidities are present and are posited as a primary mechanism of muscle dysfunction. Objective: To investigate skeletal muscle function and morphology across the adult lifespan in those with an...

RNA-binding proteins (RBPs) are essential for post-transcriptional regulation and processing of RNAs. Pathogenic missense variants in RBPs underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget's disease of the bone. Here, we present ten indepe...

An amendment to this paper has been published and can be accessed via the original article.

There are limited and equivocal data regarding potential fiber type-specific differences in the human skeletal muscle response to sprint interval training (SIT), including how this compares to moderate-intensity continuous training (MICT). We examined mixed muscle and fiber type-specific responses to a single session (study 1) and 12 wk (study 2) o...

Background: Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). Objectives: We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association...

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven...

The benefits of exercise on health and longevity are well-established, and evidence suggests that these effects are partially driven by a spectrum of bioactive molecules released into circulation during exercise (e.g., exercise factors or 'exerkines'). Recently, extracellular vesicles (EVs), including microvesicles (MVs) and exosomes or exosome-lik...

Background: GNE myopathy is a rare, autosomal recessive, muscle disease caused by mutations in GNE and is characterized by rimmed vacuoles on muscle biopsy and progressive distal to proximal muscle weakness. Objective: Investigate the clinical presentation and progression of GNE myopathy. Methods: The GNE Myopathy Disease Monitoring Program wa...

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Nav) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal s...

Mitochondrial diseases (MIDs) involve multiple organs including peripheral nerves and skeletal muscle. Mitochondrial neuropathy (MN) and mitochondrial myopathy (MM) are commonly associated and linked at the neuromuscular junction (NMJ). Herein we review MN in connection with neurogenic features of MM, and pathological evidence for the involvement o...

Reports of patients with concomitant diagnoses of two inherited genetic disorders, sometimes referred to as “double trouble,” have appeared intermittently in the medical literature. We report eight additional cases with dual diagnoses of two genetic conditions. All cases had a phenotype atypical for their primary diagnosis, leading to the search fo...

Aging results in a chronic, pro-inflammatory state which can promote and exacerbate age-associated diseases. In contrast, physical activity in older adults improves whole body health, protects against disease, and reduces inflammation, but the elderly are less active making it difficult to disentangle the effects of aging from a sedentary lifestyle...

Background Spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons causing muscle atrophy and weakness. Nusinersen, the first effective SMA therapy was approved by Health Canada in June 2017 and has been added to the provincial formulary of all but one Canadian province. Access to this effective therapy has triggered...

Hereditary spastic paraplegia is a group of rare motor neuron diseases considered to be inherited in a classical monogenic Mendelian manner. Although the typical inheritance of spastic paraplegia type 7 is autosomal recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant HSP. We aimed to conduct an exome-wide...

Background Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging. Objectives To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Cana...

Old age is associated with lower physical activity levels, suboptimal protein intake, and desensitization to anabolic stimuli, predisposing for age-related muscle loss (sarcopenia). Although resistance exercise (RE) and protein supplementation partially protect against sarcopenia under controlled conditions, the efficacy of home-based, unsupervised...

Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been shown to cau...

Type 1 diabetes (T1D) has been reported to negatively affect the health of skeletal muscle, though the underlying mechanisms are unknown. Myostatin, a myokine whose increased expression is associated with muscle‐wasting diseases, has not been reported in humans with T1D but has been demonstrated to be elevated in preclinical diabetes models. Thus,...

Studies have shown that mitochondrial DNA (mtDNA) can be exchanged between tissues; however, the mechanism(s) behind this phenomenon remain unclear. Exosomes and other extracellular vesicles (EVs) including microvesicles (MV) have been shown to contain mtDNA. EVs can be derived from a number of tissues; however, the source and relative proportion o...

[This corrects the article DOI: 10.1371/journal.pone.0210863.].

Background 2‐oxoglutarate dehydrogenase (OGDH) is a rate‐liming enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α‐ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Methods Usin...

We describe a novel mitochondrial variant (m.5865T>C) in a patient with decreased exercise endurance and juvenile onset slowly progressive bilateral ptosis without opthamloparesis. The m.5865T>C variant was seen in 82.9% of mtDNA molecules in skeletal muscle tissue and ∼8% of mtDNA molecules in urine epithelium, but was not detected in blood leukoc...

Congenital myasthenic syndromes (CMS) are caused by mutations in molecules expressed at the neuromuscular junction. We report clinical, structural, ultrastructural, and electrophysiologic features of 4 CMS patients with 6 heteroallelic variants in AGRN, encoding agrin. One was a 7.9-kb deletion involving the N-terminal laminin-binding domain. Anoth...

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

Objective To describe clinical, biochemical, and genetic features of participants with mitochondrial diseases (MtDs) enrolled in the North American Mitochondrial Disease Consortium (NAMDC) Registry. Methods This cross-sectional, multicenter, retrospective database analysis evaluates the phenotypic and molecular characteristics of participants enro...

Lipofuscin aggregation may result from incomplete degradation of damaged mitochondria by autophagy-lysosome pathway, and intra-mitochondrial lipofuscin aggregation may exacerbate mitochondrial abnormalities in mitochondrial myopathy (MM) and mitochondrial disease. We examined vastus lateralis muscle biopsies from 24 patients with pathologically dia...

PURPOSE: Inherited axonopathies (IA) are rare, clinically and genetically heterogeneous diseases that lead to length-dependent degeneration of the long axons in central (hereditary spastic paraplegia [HSP]) and peripheral (Charcot–Marie–Tooth type 2 [CMT2]) nervous systems. Mendelian high-penetrance alleles in over 100 different genes have been sho...

Purpose To assess the clinical utility of next-generation sequencing (NGS) for the diagnosis of patients with optic atrophy (OA). Design Retrospective cohort study. Methods 97 patients were referred to the McMaster University Medical Center (Hamilton, Ontario) for evaluation of bilateral OA. All patients were sent for NGS including a 22 nuclear g...

The legs of 9 men (age 21 ± 2 years, 45 ± 4 mL/(kg·min)) were randomly assigned to complete 6 sessions of high-intensity exercise training, involving either one or four 5-min bouts of counterweighted, single-leg cycling. Needle biopsies from vastus lateralis revealed that citrate synthase maximal activity increased after training in the 4-bout grou...

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 pote...

Chronic progressive external ophthalmoplegia (CPEO) is a common presentation of mitochondrial disease. We performed a retrospective evaluation of the molecular genetic testing and genotype-phenotype correlations in a large cohort of adult-onset CPEO patients (N = 111). One hundred percent of patients tested had at least one mitochondrial DNA (mtDNA...

Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes (T2D). The role of the immune system in skeletal muscle (SM) inflammation and insulin sensitivity is not yet well characterized. As SM IR is an important determinant of glycaemia, it i...

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. Method...

The current standard of care for Pompe disease (PD) is the administration of enzyme replacement therapy (ERT). Exercise and nutrition are often considered as complementary strategies rather than “treatments” per se. Nutritional assessment is important in patients with locomotor disability because the relative hypodynamia limits energy expenditure a...

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse...

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WE...

Mitochondria orchestrate the life and death of most eukaryotic cells by virtue of their ability to supply adenosine triphosphate from aerobic respiration for growth, development, and maintenance of the ‘physiologic reserve’. Although their double-membrane structure and primary role as ‘powerhouses of the cell’ have essentially remained the same for...

(The American Journal of Human Genetics 104, 466–483; March 7, 2019)In the originally published version of this article, the 5′ UTR variant of Family 5 was incorrectly described; the correct substitution is chr3:g.49761246G>A. Additionally, there were two instances of incorrect reference transcripts. The variant for family 8 correctly corresponds t...

Mitochondrial diseases (MIDs) involve peripheral nerves and skeletal muscle, but the prevalence of mitochondrial neuropathy is still unclear. Mitochondrial neuropathy has been found to correlate with muscle weakness that may be due to myopathic and/or neurogenic myopathy in patients with MIDs. We examined vastus lateralis muscle biopsies of 58 cons...

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others c...