Muscle metabolic defects have been suspected as contributors toward the pathogenesis of DM. Recent studies have suggested that cellular/molecular mechanisms underlying reduced insulin sensitivity in skeletal muscle of both DM1 and DM2 may be more complex that has been appreciated. Specifically, prior findings suggested that perturbations of post-INSR signaling may be a key factor in development of insulin resistance (Renna et al., 2017). A new publication builds on these data to better establish the link between DM splicopathy and the development of insulin resistance and skeletal muscle atrophy.

Linking DM Molecular Biology to Metabolic Dysfunction

Drs. Laura Renna, Giovanni Meola, and Rosanna Cardani and colleagues (IRCCS-Policlinico San Donato and University of Milan) investigated events downstream from DM-associated mis-splicing of the insulin receptor (INSR) to identify pathways underlying insulin resistance and skeletal muscle wasting (Renna et al., 2019). Specifically, the team asked whether a lack of insulin pathway activation could contribute to skeletal muscle atrophy. Dr Renna was the recipient of an MDF Fellowship in support of this work.

The research team evaluated muscle biopsies from 8 DM1 and 3 DM2 genetically confirmed patients enrolled in a national registry. Biopsies were assessed for muscle fiber type and morphometrics, insulin receptor protein expression, INSR alternative splicing, and signaling pathway response to insulin stimulation.

Skeletal muscle atrophy was detected in nearly all DM1 (type 1 and/or type 2 fiber atrophy) and DM2 (type 2 fiber atrophy) patients. In contrast to the pattern seen in controls (including samples from unaffected controls, motoneuron disease, and type 2 diabetics), RT-PCR analysis showed predominance of the fetal insulin receptor isoform transcript in both types of DM. When examined by fiber type, DM skeletal muscle exhibited a lower expression of insulin receptor protein than all controls for type 1 (slow oxidative) muscle fibers. The team found a negative correlation between type 1 fiber insulin receptor protein level and level of fetal insulin receptor transcript.

A means of assessing insulin pathway activation was identified and validated by the research team. Their results showed that defective activation of insulin signaling led to lower activation of mTOR accompanied by increases in MuRF1 and Atrogin-1/MAFbx expression—all key regulators known to act through insulin signaling to modulate skeletal muscle mass.

Modeling the Impact on Skeletal Muscle in DM

Taken together, these findings further advance understanding of the linkage between insulin receptor mis-splicing, metabolic dysfunction, and skeletal muscle atrophy. In terms of the insulin receptor, predominance of the fetal insulin receptor isoform in DM was observed, and an overall reduction in insulin receptor protein level in DM skeletal muscles was linked to reductions in receptor expression in type 1 fibers.

Based on these data, the research team suggests that reduced insulin receptor levels are responsible for the observed defect in insulin pathway activation in DM and a metabolic imbalance in protein synthesis/degradation—these, in turn, indicate a potential link to skeletal muscle weakness and atrophy, but causality has not yet been established.

Finally, another recent publication (Vujnic et al., 2018) expands upon this theme of metabolic dysfunction in DM, reporting an increased incidence of metabolic syndrome (i.e., co-occurrence of at least 3 of 5 symptoms: central obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein) in DM2. Thus, there’s a clear case for increased research and patient management efforts directed toward metabolic dysfunction in DM.

References:

Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.
Renna LV, Bosè F, Iachettini S, Fossati B, Saraceno L, Milani V, Colombo R, Meola G, Cardani R.
PLoS One. 2017 Sep 15;12(9):e0184987. doi: 10.1371/journal.pone.0184987. eCollection 2017.

Aberrant insulin receptor expression is associated with insulin resistance and skeletal muscle atrophy in myotonic dystrophies.
Renna LV, Bosè F, Brigonzi E, Fossati B, Meola G, Cardani R.
PLoS One. 2019 Mar 22;14(3):e0214254. doi: 10.1371/journal.pone.0214254. eCollection 2019.

Metabolic impairments in patients with myotonic dystrophy type 2.
Vujnic M, Peric S, Calic Z, Benovic N, Nisic T, Pesovic J, Savic-Pavicevic D, Rakocevic-Stojanovic V.
Acta Myol. 2018 Dec 1;37(4):252-256. eCollection 2018 Dec.

Presented at the 2024 MDF Regional Conference on Saturday, May 4, 2024 at the Dunn Tower at Houston Methodist in Houston, TX.

Learn about nutrition and swallowing difficulties in myotonic dystrophy. The session will cover adaptive eating techniques and dietary recommendations that cater to the unique swallowing challenges faced by individuals with DM. Gain practical guidance on enhancing nutritional intake and managing dysphagia, improving overall health and daily functioning.

Speakers: Anna Miller, MS, RD, LD, Senior Clinical Dietitian & Carolyn Martinez, M.A., CCC-SLP, Speech Pathologist, Houston Methodist

Click here to learn more about the 2024 MDF Regional Conference in in Houston, TX!

Presented at the MDF 2024 Regional Conference in Gainesville, FL, on Saturday, March 23, 2024 at the Harrell Medical Education Building at the University of Florida.

Learn how moderate exercise can be safe and helpful for people with myotonic dystrophy. Learn about the latest studies on DM and exercise, how to choose exercises with your healthcare team, and some examples of DM-friendly exercises.

Speaker: Donovan J. Lott, PT, PhD, CSCS, Research Professor, Department of Physical Therapy, University of Florida

Click here to learn more about the 2024 MDF Regional Conference in Gainesville, FL at!

Exercise, Nutrition & Speech with Katy Eichinger, PhD, DPT, Leslie Vnenchak, MA, CCC-SLP, and Robin Meyers, RD, MPH, LDN

This rehabilitation panel reviews current research and strategies for managing DM symptoms through exercise, speech and nutrition.

Download the Exercise Slide Deck.

Download the Speech Slide Deck.

Download the Nutrition Slide Deck.

Gene Editing for DM

Gene editing has garnered considerable publicity as the newest technology with potential for developing therapies for rare diseases. MDF previously published a primer, titled "Using Gene Editing to Correct DM," on the CRISPR/Cas9 technology that has been heavily promoted in the media.

Gene editing technology uses molecular mechanisms that were first developed in bacteria as a shield against invasion from viruses. This approach is rapidly moving into clinical trials for a select group of diseases—those where cells can be isolated from the body, edited, and then returned to patients as a viable treatment for the disease. These diseases are predominantly disorders of the blood and cancers, and several clinical trials are recruiting patients in China (HIV-infected subjects with hematological malignances; CD19+ refractory leukemia/lymphoma; esophageal cancer; metastatic non-small cell lung cancer; EBV-associated malignancies). At least one trial has been approved in the U.S. by the Food and Drug Administration (FDA) and is expected to start soon (this is also for a set of cancers).

For myotonic dystrophy (DM), multiple organ systems are affected and we cannot take the simple path of editing and returning cells to the body—treatment must address simply too much body tissue mass, including the brain, the heart, skeletal muscles, the gastrointestinal system, and other organs that are affected. Thus, for CRISPR/Cas9 to “work” in DM, the gene editing reagents will have to be efficiently delivered to virtually every cell in patients and effectively execute the deletion of CTG and CCTG repeat expansions from the DNA. The delivery of gene editing reagents into patients is an incredibly difficult undertaking and is likely years away from clinical trials in any disease.

Could a Modified CRISPR Technology be Effective in DM?

Investigators at the University of California San Diego, the University of Florida, and the National University of Singapore have recently reported early research that potentially ‘repurposes’ gene editing technology for a set of RNA disorders—myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), a subset of Lou Gehrig’s disease (ALS) patients and Huntington’s disease. They have modified the Cas9 enzyme so it is targeted to toxic RNA, instead of the expanded DNA repeats in these diseases.

The researchers have optimized Cas9 so that it can specifically target and degrade expanded repeat RNA for DMPK and CNBP genes. In many ways, this is similar to the approach that Ionis Pharma is using to target CUG repeats RNA in DM1. 

Their development of an RNA-targeted Cas9 results in the degradation of toxic RNA, an increase in the MBNL protein, and reduction or elimination of the gene splicing defect that characterizes DM. The strategy uses gene therapy vectors to delivery the modified Cas9 enzyme. If this approach were to be effective, it’s likely that patients would only need a single intravenous injection to treat skeletal muscles, the heart, and the gastrointestinal system; because gene therapy does not cross the blood brain barrier, a second injection may be needed, into the fluid around the spinal cord, to treat the brain. To work toward clinical development, the researchers have formed a biotechnology company to raise funding and move the candidate therapy forward.

We Still Have a Considerable Way to Go Before this Novel Strategy is in the Clinic

While this approach shows promise, we should be cautioned that studies thus far have only tried the new experimental therapy in patient cells in tissue culture. Therapy development has to pass through preclinical testing in appropriate mouse models, preclinical safety testing and approval by the FDA before the first clinical trial can be launched. Importantly, this effort represents yet another shot on goal to develop a novel therapeutic for DM1 and DM2. MDF monitors all drug development efforts and will keep the community informed as to their progress.

Accurate assessment of endpoints that are clinically meaningful to the patient is essential for the regulatory approval of a candidate therapeutic. Many of the endpoints used in clinical trials for myotonic dystrophy (DM) type 1 (DM1) thus far do not meet this requirement and thus do not represent adequate registration endpoints. Such registration endpoints are the holy grail for DM. Tools must be validated to assess the diverse factors that contribute to fatigue in order to develop clinical trial endpoints and effective therapies.

Baldanzi and colleagues (University of Pisa) have published an evaluation of several instruments in a cohort of 26 subjects with the genetic and clinical diagnosis of DM1 and proposed a paradigm to assess central and peripheral fatigue. They defined central fatigue as a decrement in voluntary muscle activation during exercise related to cognitive/behavioral function. By contrast, peripheral fatigue was characterized as the consequence of altered transmission at the neuromuscular junction or muscular dysfunction. The authors suggest a protocol for evaluation as an assessment of fatigue in DM1. 

Fatigue is an important contributor to patient-reported burden of disease in DM1. However, across neuromuscular diseases, there has been considerable debate around both defining and measuring fatigue.

Objectively, fatigue is defined as a decrease in power (work performed over time). Fatigue may arise from having to operate at or near one’s maximal motor functional capacity—diminishment of that capacity leads to early onset of fatigue. Yet, another important disease burden in DM2, pain, limits the performance of work and thus the measurement of fatigue is confounded as patients may not want to exert maximal effort due to the discomfort it causes. 

Since patients are able to detect even subtle changes in fatigue, patient reported outcome measures (PROMs) have potential as clinical trial endpoints. Fatigue can have both central and peripheral origins, and its dual origin may impact therapy development strategies. Thus, for a multi-systemic disease like DM, it is particularly important that we have tools to quantitatively evaluate fatigue regardless of origin and, optimally, gain some insights into peripheral and central contributions. A PROM scale such as the Modified Fatigue Impact Scale (MFIS) has three subscales (physical, cognitive, and psychosocial functioning) that may, in part, help understand fatigue. Another commonly used scale, the Multidimensional Assessment of Fatigue (MAF), is valuable in assessing four dimensions of fatigue—degree and severity, distress caused, timing and impact on activities of daily living.

Because fatigue is multifactorial, studies are needed to evaluate and validate measures of fatigue. The Myotonic Dystrophy Health Index (MDHI) is a PROM that has been incorporated into many recent clinical studies and trials and includes separate question banks that assess fatigue, sleep, and cognition. Its fatigue component is thought to focus on muscle fatigue, muscle endurance, and “tiredness” arising from muscle. The sleep and cognitive components have been linked to CNS-based fatigue, including motivation and concentration. 

The complex etiology of fatigue in DM1 makes it difficult for individual instruments to dissect peripheral and central components of fatigue. Given its key role in the burden of DM, it is critical that validated measures of fatigue be incorporated into natural history studies and clinical trials. 

Reference:

The proposal of a clinical protocol to assess central and peripheral fatigue in myotonic dystrophy type 1.
Baldanzi S, Ricci G, Bottari M, Chico L, Simoncini C, Siciliano G.
Arch Ital Biol. 2017 Jul 1;155(1-2):43-54. doi: 10.12871/000398292017125.

MDF’s Patient-Focused Drug Development (PFDD) meeting, held in 2016 in conjunction with the U.S. Food and Drug Administration (FDA), highlighted the critical role of patients in developing clinically-meaningful outcome measures to facilitate drug development and approval. Identification of the symptoms regarded as most important to patients and caregivers, and the benefits they would most hope to derive from a therapy, provides critical guidance that must be included from the earliest stages of drug development.

Patient registries, like MDF’s Myotonic Dystrophy Family Registry, the National Registry for Myotonic Dystrophy & Facioscapulohumeral Dystrophy at the University of Rochester, the DM-Scope Registry in France, and the UK Myotonic Dystrophy Patient Registry, represent critically important data repositories to facilitate studies of the burden of disease for those living with myotonic dystrophy (DM).

The UK DM Patient Registry published a cross-sectional analysis of self-reported data from 556 myotonic dystrophy type 1 (DM1) patients with a confirmed diagnosis, representing approximately 8.5% of the estimated affected population in the United Kingdom (UK). Registered patients were also able to nominate healthcare specialists to enter their genetic and clinical data; these data augmented patient profiles and served to validate the patient-reported registry format.

Registrant gender was equally distributed (51% female) and a positive family history of DM was reported by 89% of registrants. Mean age of onset was 33 years. Fatigue/daytime sleepiness (79%) and myotonia (78%) were the most frequently reported symptoms—the occurrence of myotonia positively correlated with fatigue, dysphagia and ambulatory status. As in a prior report by the DM-Scope Registry, the UK cohort showed a higher frequency of severe myotonia in males, although fatigue did not show gender bias. Men also reported a higher frequency of cardiac abnormalities, non-invasive ventilation, and mobility impairments, while cataract surgery was more common in women. Most patients (65%) did not require assistive devices to walk. Severity of symptoms did not correlate with CTG repeat length obtained at the time of genetic testing.

While only one-third of patients reported having EKG, 48% of those were diagnosed with a cardiac conduction system abnormality and 36% had received an implanted cardiac device. Non-invasive ventilation was used regularly by 15% of patients. Of the patients with data available, 26% reported cataract surgery.

The UK group reported that the delays in receiving a genetic diagnosis of DM1 remain substantial and do not seem to have improved since the advent of genetic testing in 1996. They stress the importance of reducing the genetic diagnostic odyssey, not only to improve patient care and quality of life, but also to facilitate community readiness for interventional trials and approved therapies.

Taken together, knowledge of the symptoms that are most important to DM1 patients provides guidance not only for improved care, but also for the development of novel therapeutics. Studies such as that reported here, from the UK registry, provide an evidence-based underpinning that is essential for progress. An improved collaborative environment, whereby registry data is more readily shared, is a goal that will not only improve the science, but is in the best interests of those living with DM.

Reference:

The UK Myotonic Dystrophy Patient Registry: Facilitating and Accelerating Clinical Research
Wood L, Cordts I, Atalaia A, Marini-Bettolo C, Maddison P, Phillips M, Roberts M, Rogers M, Hammans S, Straub V, Petty R, Orrell R, Monckton DG, Nikolenko N, Jimenez-Moreno AC, Thompson R, Hilton-Jones D, Turner C, Lochmüller H.
J Neurol. 2017 Apr 10. doi: 10.1007/s00415-017-8483-2. [Epub ahead of print]